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1. Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate

Author: Thorsten Schaefer, Nitish Mittal, Hui Wang, Meric Ataman, Silvia Candido, Jonas Lötscher, Sergiy Velychko, Lionel Tintignac, Thomas Bock, Anastasiya Börsch, Jochen Baßler, Tata Nageswara Rao, Jakub Zmajkovic, Sarah Roffeis, Jordan Löliger, Francis Jacob, Alain Dumlin, Christoph Schürch, Alexander Schmidt, Radek C. Skoda, Matthias P. Wymann, Christoph Hess, Hans R. Schöler, Holm Zaehres, Ed Hurt, Mihaela Zavolan, and Claudia Lengerke
Subjects: CP: Developmental biology, CP: Molecular biology, Biology (General), QH301-705.5
Abstract: Summary: Stemness and pluripotency are mediated by transcriptional master regulators that promote self-renewal and repress cell differentiation, among which is the high-mobility group (HMG) box transcription factor SOX2. Dysregulated SOX2 expression, by contrast, leads to transcriptional aberrations relevant to oncogenic transformation, cancer progression, metastasis, therapy resistance, and relapse. Here, we report a post-transcriptional mechanism by which the cytosolic pool of SOX2 contributes to these events in an unsuspected manner. Specifically, a low-complexity region within SOX2’s C-terminal segment connects to the ribosome to modulate the expression of cognate downstream factors. Independent of nuclear structures or DNA, this C-terminal functionality alone changes metabolic properties and induces non-adhesive growth when expressed in the cytosol of SOX2 knockout cells. We thus propose a revised model of SOX2 action where nuclear and cytosolic fractions cooperate to impose cell fate decisions via both transcriptional and translational mechanisms.
Published: 2024
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2. Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition

Author: Patrick M. Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S. Gabriel, David P. de Souza, Christoph Hess, Malcolm M. McConville, Daniel T. Utzschneider, and Axel Kallies
Subjects: CP: Cancer, CP: Metabolism, Biology (General), QH301-705.5
Abstract: Summary: Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.
Published: 2024
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3. A compact gas attenuator for the SwissFEL ATHOS beamline realized using additive manufacturing

Author: Claude Pradervand, Colette Rosenberg, Hans-Jörg Eckerlin, Kirsten Schnorr, Andre Al Haddad, Peter Wiegand, Christoph Hess, Nazareno Gaiffi, and Luc Patthey
Subjects: x-ray free-electron lasers, gas attenuator, additive manufacturing, Nuclear and particle physics. Atomic energy. Radioactivity, QC770-798, Crystallography, QD901-999
Abstract: Gas attenuators are important devices providing accurate variation of photon intensity for soft X-ray beamlines. In the SwissFEL ATHOS beamline front-end the space is very limited and an innovative approach has been taken to provide attenuation of three orders of magnitude up to an energy of 1200 eV. Additive manufacturing of a differential pumping system vacuum manifold allowed a triple pumping stage to be realized in a space of less than half a meter. Measurements have shown that the response of the device is as expected from theoretical calculations.
Published: 2023
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4. Frequency and impact on renal transplant outcomes of urinary tract infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species

Author: Jakob E. Brune, Michael Dickenmann, Daniel Sidler, Laura N. Walti, Déla Golshayan, Oriol Manuel, Fadi Haidar, Dionysios Neofytos, Aurelia Schnyder, Katia Boggian, Thomas F. Mueller, Thomas Schachtner, Nina Khanna, Stefan Schaub, Caroline Wehmeier, the Swiss Transplant Cohort Study, Patrizia Amico, John-David Aubert, Adrian Bachofner, Vanessa Banz, Sonja Beckmann, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Annalisa Berzigotti, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Anne Cairoli, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Sophie De Seigneux, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Jaromil Frossard, Christian Garzoni, Nicolas Goossens, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Linard Hoessly, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Michael Koller, Andreas Kremer, Christian Kuhn, Bettina Laesser, Frédéric Lamoth, Roger Lehmann, Alexander Leichtle, Hans-Peter Marti, Michele Martinelli, Valérie McLin, Katell Mellac, Aurélia Merçay, Karin Mettler, Nicolas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual, Jakob Passweg, Rosemarie Pazeller, Klara Posfay-Barbe, David Reineke, Juliane Rick, Anne Rosselet, Simona Rossi, Rössler, Silvia Rothlin, Frank Ruschitzka, Alexandra Scherrer, Dominik Schneidawind, Macé Schuurmans, Simon Schwab, Thierry Sengstag, Federico Simonetta, Jürg Steiger, Guido Stirniman, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Madeleine Wick, Markus Wilhlem, and Patrick Yerly
Subjects: kidney transplantation, urinary tract infection, Enterobacterales, E. coli, Klebsiella, ESBL − extended-spectrum beta-lactamase, Medicine (General), R5-920
Abstract: BackgroundEnterobacterales are often responsible for urinary tract infection (UTI) in kidney transplant recipients. Among these, Escherichia coli or Klebsiella species producing extended-spectrum beta-lactamase (ESBL) are emerging. However, there are only scarce data on frequency and impact of ESBL-UTI on transplant outcomes.MethodsWe investigated frequency and impact of first-year UTI events with ESBL Escherichia coli and/or Klebsiella species in a prospective multicenter cohort consisting of 1,482 kidney transplants performed between 2012 and 2017, focusing only on 389 kidney transplants having at least one UTI with Escherichia coli and/or Klebsiella species. The cohort had a median follow-up of four years.ResultsIn total, 139/825 (17%) first-year UTI events in 69/389 (18%) transplant recipients were caused by ESBL-producing strains. Both UTI phenotypes and proportion among all UTI events over time were not different compared with UTI caused by non-ESBL-producing strains. However, hospitalizations in UTI with ESBL-producing strains were more often observed (39% versus 26%, p = 0.04). Transplant recipients with first-year UTI events with an ESBL-producing strain had more frequently recurrent UTI (33% versus 18%, p = 0.02) but there was no significant difference in one-year kidney function as well as longer-term graft and patient survival between patients with and without ESBL-UTI.ConclusionFirst-year UTI events with ESBL-producing Escherichia coli and/or Klebsiella species are associated with a higher need for hospitalization but do neither impact allograft function nor allograft and patient survival.
Published: 2024
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5. Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting

Author: Milton Pereira, Jonathan Liang, Joy Edwards-Hicks, Allison M. Meadows, Christine Hinz, Sonia Liggi, Matthias Hepprich, Jonathan M. Mudry, Kim Han, Julian L. Griffin, Iain Fraser, Michael N. Sack, Christoph Hess, and Clare E. Bryant
Subjects: CP: Metabolism, CP: Immunology, Biology (General), QH301-705.5
Abstract: Summary: Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.
Published: 2024
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6. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Author: Marcel P. Trefny, Nicole Kirchhammer, Priska Auf der Maur, Marina Natoli, Dominic Schmid, Markus Germann, Laura Fernandez Rodriguez, Petra Herzig, Jonas Lötscher, Maryam Akrami, Jane C. Stinchcombe, Michal A. Stanczak, Andreas Zingg, Melanie Buchi, Julien Roux, Romina Marone, Leyla Don, Didier Lardinois, Mark Wiese, Lukas T. Jeker, Mohamed Bentires-Alj, Jérémie Rossy, Daniela S. Thommen, Gillian M. Griffiths, Heinz Läubli, Christoph Hess, and Alfred Zippelius
Subjects: Science
Abstract: The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
Published: 2023
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7. Donation type and the effect of pre-transplant donor specific antibodies – Data from the Swiss Transplant Cohort Study

Author: Olivier de Rougemont, Yun Deng, Lukas Frischknecht, Caroline Wehmeier, Jean Villard, Sylvie Ferrari-Lacraz, Déla Golshayan, Monique Gannagé, Isabelle Binet, Urs Wirthmueller, Daniel Sidler, Thomas Schachtner, Stefan Schaub, Jakob Nilsson, the Swiss Transplant Cohort Study, Patrizia Amico, Andres Axel, John David Aubert, Vanessa Banz, Beckmann Sonja, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Olivier De Rougemont, Michael Dickenmann, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Nicola Franscini, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Nicolas Goossens, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Michael Koller, Mirjam Laager, Bettina Laesser, Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Michele Martinelli, Valérie McLin, Katell Mellac, Aurelia Mercay, Karin Mettler, Nicolas Mueller, Antonia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual, Klara Posfay-Barbe, Juliane Rick, Anne Rosselet, Simona Rossi, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Aurelia Schnyder, Macé Schuurmans, Thierry Sengstag, Federico Simonetta, Katharina Staufer, Susanne Stampf, Jürg Steiger, Guido Stirniman, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Julien Vionnet, Madeleine Wick, Markus Wilhlem, and Patrick Yerly
Subjects: kidney transplantation, donor specific antibodies, ABMR, graft loss, virtual cross-match, living donation, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionThe type of donation may affect how susceptible a donor kidney is to injury from pre-existing alloimmunity. Many centers are, therefore, reluctant to perform donor specific antibody (DSA) positive transplantations in the setting of donation after circulatory death (DCD). There are, however, no large studies comparing the impact of pre-transplant DSA stratified on donation type in a cohort with a complete virtual cross-match and long-term follow-up of transplant outcome.MethodsWe investigated the effect of pre-transplant DSA on the risk of rejection, graft loss, and the rate of eGFR decline in 1282 donation after brain death (DBD) transplants and compared it to 130 (DCD) and 803 living donor (LD) transplants.ResultsThere was a significant worse outcome associated with pre-transplant DSA in all of the studied donation types. DSA directed against Class II HLA antigens as well as a high cumulative mean fluorescent intensity (MFI) of the detected DSA showed the strongest association with worse transplant outcome. We could not detect a significant additive negative effect of DSA in DCD transplantations in our cohort. Conversely, DSA positive DCD transplants appeared to have a slightly better outcome, possibly in part due to the lower mean fluorescent intensity (MFI) of the pre-transplant DSA. Indeed when DCD transplants were compared to DBD transplants with similar MFI (
Published: 2023
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8. Forced expression of the non-coding RNA miR-17∼92 restores activation and function in CD28-deficient CD4+ T cells

Author: Marianne Dölz, Marko Hasiuk, John D. Gagnon, Mara Kornete, Romina Marone, Glenn Bantug, Robin Kageyama, Christoph Hess, K. Mark Ansel, Denis Seyres, Julien Roux, and Lukas T. Jeker
Subjects: Biological sciences, molecular mechanism of gene regulation, immunology, Science
Abstract: Summary: CD28 provides the prototypical costimulatory signal required for productive T-cell activation. Known molecular consequences of CD28 costimulation are mostly based on studies of protein signaling molecules. The microRNA cluster miR-17∼92 is induced by T cell receptor stimulation and further enhanced by combined CD28 costimulation. We demonstrate that transgenic miR-17∼92 cell-intrinsically largely overcomes defects caused by CD28 deficiency. Combining genetics, transcriptomics, bioinformatics, and biochemical miRNA:mRNA interaction maps we empirically validate miR-17∼92 target genes that include several negative regulators of T cell activation. CD28-deficient T cells exhibit derepressed miR-17∼92 target genes during activation. CRISPR/Cas9-mediated ablation of the miR-17∼92 targets Pten and Nrbp1 in naive CD28−/− CD4+ T cells differentially increases proliferation and expression of the activation markers CD25 and CD44, respectively. Thus, we propose that miR-17∼92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation by dampening multiple brakes that prevent T cell activation.
Published: 2022
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9. Enforcing GLUT3 expression in CD8+ T cells improves fitness and tumor control by promoting glucose uptake and energy storage

Author: Elisabetta Cribioli, Greta Maria Paola Giordano Attianese, Pierpaolo Ginefra, Amandine Signorino-Gelo, Romain Vuillefroy de Silly, Nicola Vannini, Christoph Hess, Melita Irving, and George Coukos
Subjects: T cell engineering, metabolism, glucose, immunotherapy, tumor, adoptive cell therapy, Immunologic diseases. Allergy, RC581-607
Abstract: Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells. Overexpression of GLUT3 in primary murine CD8+ T cells enhanced glucose uptake and increased glycogen and fatty acid storage, and was associated with increased mitochondrial fitness, reduced ROS levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress. Importantly, GLUT3-OT1 T cells conferred superior control of B16-OVA melanoma tumors and, in this same model, significantly improved survival. Moreover, a proportion of treated mice were cured and protected from re-challenge, indicative of long-term T cell persistence and memory formation. Enforcing expression of GLUT3 is thus a promising strategy to improve metabolic fitness and sustaining CD8+ T cell effector function in the context of ACT.
Published: 2022
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10. The impact of pre-transplant donor specific antibodies on the outcome of kidney transplantation – Data from the Swiss transplant cohort study

Author: Lukas Frischknecht, Yun Deng, Caroline Wehmeier, Olivier de Rougemont, Jean Villard, Sylvie Ferrari-Lacraz, Déla Golshayan, Monique Gannagé, Isabelle Binet, Urs Wirthmueller, Daniel Sidler, Thomas Schachtner, Stefan Schaub, Jakob Nilsson, the Swiss Transplant Cohort Study, Patrizia Amico, Andres Axel, John David Aubert, Vanessa Banz, Beckmann Sonja, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Olivier De Rougemont, Michael Dickenmann, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Nicola Franscini, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Nicolas Goossens, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Michael Koller (Head of the data center), Mirjam. Laager, Bettina Laesser, Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Michele Martinelli, Valérie McLin, Katell Mellac, Aurelia Mercay, Karin Mettler, Nicolas Mueller (Chairman Scientific Committee), Antonia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual (Executive office), Klara Posfay-Barbe, Juliane Rick, Anne Rosselet, Simona Rossi, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Aurelia Schnyder, Macé Schuurmans, Thierry Sengstag, Federico Simonetta, Katharina Staufer, Susanne Stampf, Jürg Steiger (Head, Excecutive office), Guido Stirniman, Ueli Stürzinger, Christian Van Delden (Executive office), Jean-Pierre Venetz, Julien Vionnet,Madeleine Wick (STCS coordinator), Markus Wilhlem, and Patrick Yerly
Subjects: kidney transplantation, donor specific antibodies, abmr, graft loss, virtual cross-match, Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundPre-transplant donor specific antibodies (DSA), directed at non-self human leukocyte antigen (HLA) protein variants present in the donor organ, have been associated with worse outcomes in kidney transplantation. The impact of the mean fluorescence intensity (MFI) and the target HLA antigen of the detected DSA has, however, not been conclusively studied in a large cohort with a complete virtual cross-match (vXM).MethodsWe investigated the effect of pre-transplant DSA on the risk of antibody-mediated rejection (ABMR), graft loss, and the rate of eGFR decline in 411 DSA positive transplants and 1804 DSA negative controls.ResultsPre-transplant DSA were associated with a significantly increased risk of ABMR, graft loss, and accelerated eGFR decline. DSA directed at Class I and Class II HLA antigens were strongly associated with increased risk of ABMR, but only DSA directed at Class II associated with graft loss. DSA MFI markedly affected outcome, and Class II DSA were associated with ABMR already at 500-1000 MFI, whereas Class I DSA did not affect outcome at similar low MFI values. Furthermore, isolated DSA against HLA-DP carried comparable risks for ABMR, accelerated eGFR decline, and graft loss as DSA against HLA-DR.ConclusionOur results have important implications for the construction and optimization of vXM algorithms used within organ allocation systems. Our data suggest that both the HLA antigen target of the detected DSA as well as the cumulative MFI should be considered and that different MFI cut-offs could be considered for Class I and Class II directed DSA.
Published: 2022
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11. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Author: Jennifer K. Dowling, Remsha Afzal, Linden J. Gearing, Mariana P. Cervantes-Silva, Stephanie Annett, Gavin M. Davis, Chiara De Santi, Nadine Assmann, Katja Dettmer, Daniel J. Gough, Glenn R. Bantug, Fidinny I. Hamid, Frances K. Nally, Conor P. Duffy, Aoife L. Gorman, Alex M. Liddicoat, Ed C. Lavelle, Christoph Hess, Peter J. Oefner, David K. Finlay, Gavin P. Davey, Tracy Robson, Annie M. Curtis, Paul J. Hertzog, Bryan R. G. Williams, and Claire E. McCoy
Subjects: Science
Abstract: IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
Published: 2021
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12. The impact of hypoxia on B cells in COVID-19

Author: Prasanti Kotagiri, Federica Mescia, Aimee L. Hanson, Lorinda Turner, Laura Bergamaschi, Ana Peñalver, Nathan Richoz, Stephen D. Moore, Brian M. Ortmann, Benjamin J. Dunmore, Michael D. Morgan, Zewen Kelvin Tuong, Berthold Göttgens, Mark Toshner, Christoph Hess, Patrick. H. Maxwell, Menna. R. Clatworthy, James A. Nathan, John R. Bradley, Paul A. Lyons, Natalie Burrows, and Kenneth G.C. Smith
Subjects: COVID-19, Hypoxia, B cells, Lymphopenia, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. Methods: Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice. Findings: We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions. Interpretation: Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes. Funding: Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust
Published: 2022
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13. Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Author: Elizabeth Rivers, Rajeev Rai, Jonas Lötscher, Michael Hollinshead, Gasper Markelj, James Thaventhiran, Austen Worth, Alessia Cavazza, Christoph Hess, Mona Bajaj-Elliott, and Adrian J Thrasher
Subjects: Wiskott Aldrich syndrome, actin cytoskeleton, immunometabolism, autophagy, innate immune cells, Medicine, Science, Biology (General), QH301-705.5
Abstract: The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
Published: 2020
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14. Distinct Transcriptional Responses across Tissue-Resident Macrophages to Short-Term and Long-Term Metabolic Challenge

Author: Urszula Brykczynska, Marco Geigges, Sophia J. Wiedemann, Erez Dror, Marianne Böni-Schnetzler, Christoph Hess, Marc Y. Donath, and Renato Paro
Subjects: Biology (General), QH301-705.5
Abstract: Summary: The innate immune system safeguards the organism from both pathogenic and environmental stressors. Also, physiologic levels of nutrients affect organismal and intra-cellular metabolism and challenge the immune system. In the long term, over-nutrition leads to low-grade systemic inflammation. Here, we investigate tissue-resident components of the innate immune system (macrophages) and their response to short- and long-term nutritional challenges. We analyze the transcriptomes of six tissue-resident macrophage populations upon acute feeding and identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes. Furthermore, by comparing functional responses between macrophage subtypes, we propose a regulatory, anti-inflammatory role of heat shock proteins of the HSP70 family in response to long- and short-term metabolic challenges. Our data provide a resource for assessing the impact of nutrition and over-nutrition on the spectrum of macrophages across tissues with a potential for identification of systemic responses. : Brykczynska et al. investigate the response of tissue-resident macrophages to short- and long-term nutritional challenges. They identify adipose tissue macrophages and the IL-1 pathway as early sensors of metabolic changes and propose a regulatory role for heat shock proteins in response to acute and chronic metabolic perturbances. Keywords: macrophages, obesity, diabetes, high fat diet, postprandial, IL-1, HSP
Published: 2020
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15. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

Author: Laura Pisarsky, Ruben Bill, Ernesta Fagiani, Sarah Dimeloe, Ryan William Goosen, Jörg Hagmann, Christoph Hess, and Gerhard Christofori
Subjects: Biology (General), QH301-705.5
Abstract: Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.
Published: 2016
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16. The heart in systemic lupus erythematosus - A comprehensive approach by cardiovascular magnetic resonance tomography.

Author: Thilo Burkard, Marten Trendelenburg, Thomas Daikeler, Christoph Hess, Jens Bremerich, Philip Haaf, Peter Buser, and Michael J Zellweger
Subjects: Medicine, Science
Abstract: BACKGROUND:In systemic lupus erythematosus (SLE), cardiac manifestations, e.g. coronary artery disease (CAD) and myocarditis are leading causes of morbidity and mortality. The prevalence of subclinical heart disease in SLE is unknown. We studied whether a comprehensive cardiovascular magnetic resonance (CMR) protocol may be useful for early diagnosis of heart disease in SLE patients without known CAD. METHODS:In this prospective, observational, cross-sectional study CMR including cine, late gadolinium enhancement (LGE) and stress perfusion sequences, ECG, and blood sampling were performed in 30 consecutive SLE patients without known CAD. All patients fulfilled at least 4/11 American College of Rheumatology (ACR) Criteria for the classification of SLE. RESULTS:30 patients (83% female) were enrolled, mean age was 45±14 years and mean SLE disease duration was 10±8 years. 80% had low to moderate disease activity. All had a low SLE damage index. CMR was abnormal in 13/30 (43%), showing LGE in 9/13, stress perfusion deficits in 5/13 and pericardial effusion (PE) in 7/13. Patients with non-ischemic LGE had more often microalbuminuria while patients with stress perfusion deficits a history of hypertension, renal disorder as ACR criterion, repolarisation abnormalities on ECG and larger LV enddiastolic volume index. There was no correlation between clinical symptoms and CMR results. CONCLUSION:Our study shows that cardiac involvement as observed by CMR is frequent in SLE and not necessarily associated with typical symptoms. CMR may thus help to detect subclinical cardiac involvement, which could lead to earlier treatment. Additionally we identify possible risk factors associated with cardiac involvement.
Published: 2018
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17. Editorial: Immunometabolic Regulations in Adaptive and Innate Immune Cells Shapes and Re-Directs Host Immunity

Author: Ping-Chih Ho and Christoph Hess
Subjects: immunometabolism, metabolic reprogramming, tumor microenvironment, autoimmunity, immune suppression, Immunologic diseases. Allergy, RC581-607
Published: 2017
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18. Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels.

Author: Marc B Bigler, Simon B Egli, Cédric M Hysek, Gideon Hoenger, Laurent Schmied, Fabian S Baldin, Florian A Marquardsen, Mike Recher, Matthias E Liechti, Christoph Hess, and Christoph T Berger
Subjects: Medicine, Science
Abstract: Acute stress drives a 'high-alert' response in the immune system. Psychoactive drugs induce distinct stress hormone profiles, offering a sought-after opportunity to dissect the in vivo immunological effects of acute stress in humans.3,4-methylenedioxymethamphetamine (MDMA), methylphenidate (MPH), or both, were administered to healthy volunteers in a randomized, double-blind, placebo-controlled crossover-study. Lymphocyte subset frequencies, natural killer (NK) cell immune-phenotypes, and changes in effector function were assessed, and linked to stress hormone levels and expression of CD62L, CX3CR1, CD18, and stress hormone receptors on NK cells.MDMA/MPH > MDMA > MPH robustly induced an epinephrine-dominant stress response. Immunologically, rapid redistribution of peripheral blood lymphocyte-subsets towards phenotypically mature NK cells occurred. NK cytotoxicity was unaltered, but they expressed slightly reduced levels of the activating receptor NKG2D. Preferential circulation of mature NK cells was associated with high epinephrine receptor expression among this subset, as well as expression of integrin ligands previously linked to epinephrine-induced endothelial detachment.The acute epinephrine-induced stress response was characterized by rapid accumulation of mature and functional NK cells in the peripheral circulation. This is in line with studies using other acute stressors and supports the role of the acute stress response in rapidly mobilizing the innate immune system to counteract incoming threats.
Published: 2015
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19. Preserved antigen-specific immune response in patients with multiple sclerosis responding to IFNβ-therapy.

Author: Matthias Mehling, Stefanie Fritz, Patricia Hafner, Dominik Eichin, Tomomi Yonekawa, Thomas Klimkait, Raija L P Lindberg, Ludwig Kappos, and Christoph Hess
Subjects: Medicine, Science
Abstract: BACKGROUND: Interferon-beta (IFNβ) regulates the expression of a complex set of pro- as well as anti-inflammatory genes. In cohorts of MS patients unstratified for therapeutic response to IFNβ, normal vaccine-specific immune responses have been observed. Data capturing antigen-specific immune responses in cohorts of subjects defined by response to IFNβ-therapy are not available. OBJECTIVE: To assess antigen-specific immune responses in a cohort of MS patients responding clinically and radiologically to IFNβ. METHODS: In 26 MS patients, clinical and MRI disease activity were assessed before and under treatment with IFNβ. Humoral and cellular immune response to influenza vaccine was prospectively characterized in these individuals, and 33 healthy controls by influenza-specific Enzyme-Linked Immunosorbent Assay (ELISA) and Enzyme Linked Immuno Spot Technique (ELISPOT). RESULTS: Related to pre-treatment disease activity, IFNβ reduced clinical and radiological MS disease-activity. Following influenza vaccination, frequencies of influenza-specific T cells and concentrations of anti-influenza A and B IgM and IgG increased comparably in MS-patients and in healthy controls. CONCLUSIONS: By showing in a cohort of MS-patients responding to IFNβ vaccine-specific immune responses comparable to controls, this study indicates that antigen-specific immune responses can be preserved under successful IFNβ-therapy.
Published: 2013
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20. Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.

Author: Matthew R Henn, Christian L Boutwell, Patrick Charlebois, Niall J Lennon, Karen A Power, Alexander R Macalalad, Aaron M Berlin, Christine M Malboeuf, Elizabeth M Ryan, Sante Gnerre, Michael C Zody, Rachel L Erlich, Lisa M Green, Andrew Berical, Yaoyu Wang, Monica Casali, Hendrik Streeck, Allyson K Bloom, Tim Dudek, Damien Tully, Ruchi Newman, Karen L Axten, Adrianne D Gladden, Laura Battis, Michael Kemper, Qiandong Zeng, Terrance P Shea, Sharvari Gujja, Carmen Zedlack, Olivier Gasser, Christian Brander, Christoph Hess, Huldrych F Günthard, Zabrina L Brumme, Chanson J Brumme, Suzane Bazner, Jenna Rychert, Jake P Tinsley, Ken H Mayer, Eric Rosenberg, Florencia Pereyra, Joshua Z Levin, Sarah K Young, Heiko Jessen, Marcus Altfeld, Bruce W Birren, Bruce D Walker, and Todd M Allen
Subjects: Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract: Deep sequencing technologies have the potential to transform the study of highly variable viral pathogens by providing a rapid and cost-effective approach to sensitively characterize rapidly evolving viral quasispecies. Here, we report on a high-throughput whole HIV-1 genome deep sequencing platform that combines 454 pyrosequencing with novel assembly and variant detection algorithms. In one subject we combined these genetic data with detailed immunological analyses to comprehensively evaluate viral evolution and immune escape during the acute phase of HIV-1 infection. The majority of early, low frequency mutations represented viral adaptation to host CD8+ T cell responses, evidence of strong immune selection pressure occurring during the early decline from peak viremia. CD8+ T cell responses capable of recognizing these low frequency escape variants coincided with the selection and evolution of more effective secondary HLA-anchor escape mutations. Frequent, and in some cases rapid, reversion of transmitted mutations was also observed across the viral genome. When located within restricted CD8 epitopes these low frequency reverting mutations were sufficient to prime de novo responses to these epitopes, again illustrating the capacity of the immune response to recognize and respond to low frequency variants. More importantly, rapid viral escape from the most immunodominant CD8+ T cell responses coincided with plateauing of the initial viral load decline in this subject, suggestive of a potential link between maintenance of effective, dominant CD8 responses and the degree of early viremia reduction. We conclude that the early control of HIV-1 replication by immunodominant CD8+ T cell responses may be substantially influenced by rapid, low frequency viral adaptations not detected by conventional sequencing approaches, which warrants further investigation. These data support the critical need for vaccine-induced CD8+ T cell responses to target more highly constrained regions of the virus in order to ensure the maintenance of immunodominant CD8 responses and the sustained decline of early viremia.
Published: 2012
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21. HIV patients developing primary CNS lymphoma lack EBV-specific CD4+ T cell function irrespective of absolute CD4+ T cell counts.

Author: Olivier Gasser, Florian K Bihl, Marcel Wolbers, Elisabetta Loggi, Ingrid Steffen, Hans H Hirsch, Huldrych F Günthard, Bruce D Walker, Christian Brander, Manuel Battegay, Christoph Hess, and Swiss HIV Cohort Study
Subjects: Medicine
Abstract: BACKGROUND: In chronic HIV infection, antiretroviral therapy-induced normalization of CD4(+) T cell counts (immune reconstitution [IR]) is associated with a decreased incidence of opportunistic diseases. However, some individuals remain at risk for opportunistic diseases despite prolonged normalization of CD4(+) T cell counts. Deficient Epstein-Barr virus (EBV)-specific CD4(+) T cell function may explain the occurrence of EBV-associated opportunistic malignancy-such as primary central nervous system (PCNS) lymphoma-despite recovery of absolute CD4(+) T cell counts. METHODS AND FINDINGS: Absolute CD4(+) T cell counts and EBV-specific CD4(+) T cell-dependent interferon-gamma production were assessed in six HIV-positive individuals prior to development of PCNS lymphoma ("cases"), and these values were compared with those in 16 HIV-infected matched participants with no sign of EBV-associated pathology ("matched controls") and 11 nonmatched HIV-negative blood donors. Half of the PCNS lymphoma patients fulfilled IR criteria (defined here as CD4(+) T cell counts >or=500/microl blood). EBV-specific CD4(+) T cells were assessed 0.5-4.7 y prior to diagnosis of lymphoma. In 0/6 cases versus 13/16 matched controls an EBV-specific CD4(+) T cell response was detected (p = 0.007; confidence interval for odds ratio [0-0.40]). PCNS lymphoma patients also differed with regards to this response significantly from HIV-negative blood donors (p < 0.001, confidence interval for odds ratio [0-0.14]), but there was no evidence for a difference between HIV-negative participants and the HIV-positive matched controls (p = 0.47). CONCLUSIONS: Irrespective of absolute CD4(+) T cell counts, HIV-positive patients who subsequently developed PCNS lymphoma lacked EBV-specific CD4(+) T cell function. Larger, ideally prospective studies are needed to confirm these preliminary data, and clarify the impact of pathogen-specific versus surrogate marker-based assessment of IR on clinical outcome.
Published: 2007
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22. Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency

Author: Annaïse J. Jauch, Olivier Bignucolo, Sayuri Seki, Marie Ghraichy, Ottavia M. Delmonte, Valentin von Niederhäusern, Rebecca Higgins, Adhideb Ghosh, Masako Nishizawa, Mariko Tanaka, Adrian Baldrich, Julius Köppen, Julia R. Hirsiger, Robin Hupfer, Stephan Ehl, Anne Rensing-Ehl, Helmut Hopfer, Spasenija Savic Prince, Stephen R. Daley, Florian A. Marquardsen, Benedikt J. Meyer, Michael Tamm, Thomas D. Daikeler, Tamara Diesch, Thomas Kühne, Arthur Helbling, Caroline Berkemeier, Ingmar Heijnen, Alexander A. Navarini, Johannes Trück, Jean-Pierre de Villartay, Annette Oxenius, Christoph T. Berger, Christoph Hess, Luigi D. Notarangelo, Hiroyuki Yamamoto, and Mike Recher
Subjects: Immunology, Immunology and Allergy, 610 Medicine & health
Abstract: BACKGROUND Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4+ T cells and low TCR-Vα7.2+ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.
Published: 2023

23. SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

Author: Bo Meng, Rawlings Datir, Jinwook Choi, John R. Bradley, Kenneth G.C. Smith, Joo Hyeon Lee, Ravindra K. Gupta, Stephen Baker, Gordon Dougan, Christoph Hess, Nathalie Kingston, Paul J. Lehner, Paul A. Lyons, Nicholas J. Matheson, Willem H. Owehand, Caroline Saunders, Charlotte Summers, James E.D. Thaventhiran, Mark Toshner, Michael P. Weekes, Patrick Maxwell, Ashley Shaw, Ashlea Bucke, Jo Calder, Laura Canna, Jason Domingo, Anne Elmer, Stewart Fuller, Julie Harris, Sarah Hewitt, Jane Kennet, Sherly Jose, Jenny Kourampa, Anne Meadows, Criona O’Brien, Jane Price, Cherry Publico, Rebecca Rastall, Carla Ribeiro, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas, Ben Bullman, Benjamin J. Dunmore, Stuart Fawke, Stefan Gräf, Josh Hodgson, Christopher Huang, Kelvin Hunter, Emma Jones, Ekaterina Legchenko, Cecilia Matara, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Linda Pointon, Joy Shih, Rachel Sutcliffe, Tobias Tilly, Carmen Treacy, Zhen Tong, Jennifer Wood, Marta Wylot, Ariana Betancourt, Georgie Bower, Chiara Cossetti, Aloka De Sa, Madeline Epping, Nick Gleadall, Richard Grenfell, Andrew Hinch, Sarah Jackson, Isobel Jarvis, Ben Krishna, Francesca Nice, Ommar Omarjee, Marianne Perera, Martin Potts, Nathan Richoz, Veronika Romashova, Luca Stefanucci, Mateusz Strezlecki, Lori Turner, Eckart M.D.D. De Bie, Katherine Bunclark, Masa Josipovic, Michael Mackay, John Allison, Helen Butcher, Daniela Caputo, Debbie Clapham-Riley, Eleanor Dewhurst, Anita Furlong, Barbara Graves, Jennifer Gray, Tasmin Ivers, Emma Le Gresley, Rachel Linger, Sarah Meloy, Francesca Muldoon, Nigel Ovington, Sofia Papadia, Isabel Phelan, Hannah Stark, Kathleen E. Stirrups, Paul Townsend, Neil Walker, Jennifer Webster, Ingrid Scholtes, Sabine Hein, and Rebecca King
Subjects: Organoid, Omicron, SARS-CoV-2, Serine Endopeptidases, CP: Microbiology, COVID-19, spike, Virus Internalization, General Biochemistry, Genetics and Molecular Biology, Spike Glycoprotein, Coronavirus, NTD, Delta, Spike Glycoprotein, Coronavirus, entry, Humans, fusogenicity, TMPRSS2
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs.
Published: 2022

24. B cell receptor repertoire kinetics after SARS-CoV-2 infection and vaccination

Author: Prasanti Kotagiri, Mark R. Wills, Kelvin Hunter, William Rae, Laura Bergamaschi, Ravindra K. Gupta, John Bradley, Nicholas J Matheson, Eoin F. McKinney, Myra Hosmillo, Paul A. Lyons, Menna R. Clatworthy, Zewen Tuong, Lorinda Turner, Ian Goodfellow, Rachael Bashford-Rogers, Federica Mescia, Kenneth G. C. Smith, Federico Pehuen Pereyra Gerber, and Christoph Hess
Subjects: Resource, B cell receptor repertoire, History, medicine.medical_specialty, Polymers and Plastics, B-Cell Receptor Repertoire, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, Immunoglobulin Variable Region, Receptors, Antigen, B-Cell, Severity of Illness Index, Industrial and Manufacturing Engineering, General Biochemistry, Genetics and Molecular Biology, Clonal Evolution, Informed consent, Receptors, medicine, Immunoglobulin, Humans, Business and International Management, BNT162 Vaccine, B-Lymphocytes, business.industry, SARS-CoV-2, Repertoire, Vaccination, B-Cell, COVID-19, University hospital, SARS-CoV-2 vaccination, Immunoglobulin Heavy Chains, Immunoglobulin Isotypes, Kinetics, Somatic Hypermutation, Immunoglobulin, Spike Glycoprotein, Coronavirus, Somatic Hypermutation, Spike Glycoprotein, Coronavirus, Research centre, Family medicine, Antigen, Core laboratory, business
Abstract: B cells are important in immunity to both SARS-CoV-2 infection and vaccination, but B cell receptor (BCR) repertoire development in these contexts has not been compared. We analyse serial samples from 171 SARS-CoV-2-infected individuals and 63 vaccine recipients, and find the global BCR repertoire differs between them. Following infection, IgG1/3 and IgA1 BCRs increase, somatic hypermutation (SHM) decreases and, in severe disease, IgM and IgA clones are expanded. In contrast, after vaccination the proportion of IgD/M BCRs increase, SHM is unchanged and expansion of IgG clones is prominent. VH1-24, which targets the N-terminal domain (NTD) and contributes to neutralization, is expanded post-infection except in the most severe disease. Infection generates a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein, whilst a more focused response after vaccination mainly targets the spike’s receptor-binding domain. Thus the nature of SARS-CoV-2 exposure differentially impacts BCR repertoire development, potentially informing vaccine strategies., Graphical Abstract, Kotagiri et al. find that SARS-CoV-2 infection versus vaccination induces distinct changes in the B cell receptor repertoire, including prominent clonal expansion in IgA and IgM after infection, but IgG after vaccination. A broad anti-spike response to infection contrasts with a narrower RBD-focused one after vaccination, potentially informing vaccination strategies.
Published: 2022

25. The impact of hypoxia on B cells in COVID-19

Author: Prasanti Kotagiri, Federica Mescia, Aimee L. Hanson, Lorinda Turner, Laura Bergamaschi, Ana Peñalver, Nathan Richoz, Stephen D. Moore, Brian M. Ortmann, Benjamin J. Dunmore, Michael D. Morgan, Zewen Kelvin Tuong, Berthold Göttgens, Mark Toshner, Christoph Hess, Patrick. H. Maxwell, Menna. R. Clatworthy, James A. Nathan, John R. Bradley, Paul A. Lyons, Natalie Burrows, and Kenneth G.C. Smith
Subjects: Oxygen, B cells, Mice, SARS-CoV-2, Lymphopenia, COVID-19, Hypoxia, Animals, Humans, Pneumonia, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This presentation resembles the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19.Detailed B cell phenotyping was undertaken by flow-cytometry on longitudinal samples from patients with COVID-19 across a range of severities (NIHR Cambridge BioResource). The impact of hypoxia on the transcriptome was assessed by single-cell and whole blood RNA sequencing analysis. The direct effect of hypoxia on B cells was determined through immunisation studies in genetically modified and hypoxia-exposed mice.We demonstrate the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes also observed in B cell VHL-deficient mice. These findings were associated with hypoxia-related transcriptional changes in COVID-19 patient B cells, and similar B cell abnormalities were seen in mice kept in hypoxic conditions.Hypoxia may contribute to the pronounced and persistent B cell pathology observed in acute COVID-19 pneumonia. Assessment of the impact of early oxygen therapy on these immune defects should be considered, as their correction could contribute to improved outcomes.Evelyn Trust, Addenbrooke's Charitable Trust, UKRI/NIHR, Wellcome Trust.
Published: 2021

26. The MELD upgrade exception: a successful strategy to optimize access to liver transplantation for patients with high waiting list mortality

Author: Melisa Dirchwolf, Chiara Becchetti, Sarah G. Gschwend, Christian Toso, Philipp Dutkowski, Franz Immer, Franziska Beyeler, Simona Rossi, Jonas Schropp, Jean-François Dufour, Vanessa Banz, Patrizia Amico, Andres Axel, John-David Aubert, Beckmann Sonja, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Joëlle L. Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Paola G. Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, Jörg Halter, Dimitri Hauri, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Michael Koller, Bettina Laesser, Brian Lang, Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Y. Martin, Michele Martinelli, Katell Mellac, Aurélia Merçay, Karin Mettler, Pascal Meylan, Nicolas Mueller, Antonia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Manuel Pascual, Klara Posfay-Barbe, Juliane Rick, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Macé Schuurmans, Federico Simonetta, Katharina Staufer, Susanne Stampf, Jürg Steiger, Guido Stirniman, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Madeleine Wick, Markus Wilhlem, and Patrick Yerly
Subjects: Adult, Cohort Studies, Hepatology, Waiting Lists, Gastroenterology, Humans, Severity of Illness Index, Switzerland, Liver Transplantation
Abstract: MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland.We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates.730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p 0.001).Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.
Published: 2021

27. The impact of hypoxia on B cells in COVID-19

Author: Ravindra K. Gupta, Prasanti Kotagiri, James A. Nathan, Stephen Baker, Nicholas J Matheson, Berthold Göttgens, Paul A. Lyons, Natalie Burrows, Mark Toshner, John Bradley, Stephen Moore, Aimee Hanson, Patrick H. Maxwell, Zewen K. Tuong, Rachael Bashford Rogers, Myra Hosmillo, Christoph Hess, Ian Goodfellow, Laura Bergamaschi, Benjamin J. Dunmore, Brian Ortmann, Menna R. Clatworthy, Nathalie Kingston, Lorinda Turner, Kenneth G. C. Smith, Michael P. Weekes, Caroline Saunders, Paul J. Lehner, Hélène Ruffieux, Michael D Morgan, Sylvia Richardson, Anne Elmer, Federica Mescia, Nathan Richoz, and Ana Peñalver
Subjects: medicine.anatomical_structure, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Cancer research, medicine, Germinal center, Constitutively active, Biology, Hypoxia (medical), medicine.symptom, Marginal zone, Phenotype, B cell
Abstract: Prominent early features of COVID-19 include severe, often clinically silent, hypoxia and a pronounced reduction in B cells, the latter important in defence against SARS-CoV-2. This brought to mind the phenotype of mice with VHL-deficient B cells, in which Hypoxia-Inducible Factors are constitutively active, suggesting hypoxia might drive B cell abnormalities in COVID-19. We demonstrated the breadth of early and persistent defects in B cell subsets in moderate/severe COVID-19, including reduced marginal zone-like, memory and transitional B cells, changes we also observed in B cell VHL-deficient mice. This was corroborated by hypoxia-related transcriptional changes in COVID-19 patients, and by similar B cell abnormalities in mice kept in hypoxic conditions, including reduced marginal zone and germinal center B cells. Thus hypoxia might contribute to B cell pathology in COVID-19, and in other hypoxic states. Through this mechanism it may impact on COVID-19 outcome, and be remediable through early oxygen therapy.
Published: 2021

28. Use of induction therapy in pediatric heart transplant recipients in Switzerland - Analysis of the Swiss national database

Author: M. Schweiger, T. Erdil, S. Di Bernardo, C. Balmer, M. Yildiz, A. Kadner, Patrizia Amico, Andres Axel, John-David Aubert, Vanessa Banz, Beckmann Sonja, Guido Beldi, Christoph Berger, Ekaterine Berishvili, Isabelle Binet, Pierre-Yves Bochud, Sanda Branca, Heiner Bucher, Thierry Carrel, Emmanuelle Catana, Yves Chalandon, Sabina De Geest, Olivier De Rougemont, Michael Dickenmann, Joëlle Lynn Dreifuss, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Déla Golshayan, Nicolas Goossens, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans Hirsch, Patricia Hirt, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Michael Koller, Mirjam Laager, Bettina Laesser, Roger Lehmann, Alexander Leichtle, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Michele Martinelli, Valérie McLin, Katell Mellac, Aurélia Merçay, Karin Mettler, Nicolas Mueller, Antonia Müller, Thomas Müller, Ulrike Müller-Arndt, Beat Müllhaupt, Mirjam Nägeli, Graziano Oldani, Manuel Pascual, Klara Posfay-Barbe, Juliane Rick, Anne Rosselet, Simona Rossi, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Macé Schuurmans, Thierry Sengstag, Federico Simonetta, Katharina Staufer, Susanne Stampf, Jürg Steiger, Guido Stirniman, Ueli Stürzinger, Christian Van Delden, Jean-Pierre Venetz, Jean Villard, Julien Vionnet, Madeleine Wick, Markus Wilhlem, Patrick Yerly, Chalandon, Yves, University of Zurich, and Schweiger, M
Subjects: Graft Rejection, medicine.medical_specialty, 10255 Clinic for Thoracic Surgery, 2747 Transplantation, medicine.medical_treatment, Immunology, 610 Medicine & health, Induction therapy, Pediatric heart transplantation, Diabetes mellitus, Internal medicine, Interleukin-2 receptor antagonis, Immunology and Allergy, Medicine, Humans, Polyclonal antibodies, 10220 Clinic for Surgery, Renal replacement therapy, Child, Retrospective Studies, ddc:616, 2403 Immunology, Transplantation, business.industry, Background data, Significant difference, Induction Chemotherapy, medicine.disease, 10036 Medical Clinic, Median time, 10032 Clinic for Oncology and Hematology, 10209 Clinic for Cardiology, 2723 Immunology and Allergy, Chronic renal failure, Heart Transplantation, National database, business, Immunosuppressive Agents, Switzerland
Abstract: Background: Data on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. Method: This is a retrospective national database analysis of children
Published: 2021

29. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019

30. Magnesium sensing via LFA-1 regulates CD8

Author: Jonas, Lötscher, Adrià-Arnau, Martí I Líndez, Nicole, Kirchhammer, Elisabetta, Cribioli, Greta Maria Paola, Giordano Attianese, Marcel P, Trefny, Markus, Lenz, Sacha I, Rothschild, Paolo, Strati, Marco, Künzli, Claudia, Lotter, Susanne H, Schenk, Philippe, Dehio, Jordan, Löliger, Ludivine, Litzler, David, Schreiner, Victoria, Koch, Nicolas, Page, Dahye, Lee, Jasmin, Grählert, Dmitry, Kuzmin, Anne-Valérie, Burgener, Doron, Merkler, Miklos, Pless, Maria L, Balmer, Walter, Reith, Jörg, Huwyler, Melita, Irving, Carolyn G, King, Alfred, Zippelius, and Christoph, Hess
Subjects: Cytotoxicity, Immunologic, Male, Immunological Synapses, MAP Kinase Signaling System, Proto-Oncogene Proteins c-jun, Bacterial Infections, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Inbred C57BL, HEK293 Cells, Phenotype, Cell Line, Tumor, Neoplasms, Animals, Humans, Magnesium, Immunotherapy, Phosphorylation, Immunologic Memory, Caloric Restriction
Abstract: The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8
Published: 2021

31. Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Author: Fidinny I. Hamid, Gavin P. Davey, Paul J. Hertzog, Conor P. Duffy, Tracy Robson, Daniel J. Gough, Nadine Assmann, Katja Dettmer, Ed C. Lavelle, Christoph Hess, Anne M. Curtis, Bryan R.G. Williams, Frances K. Nally, Aoife L. Gorman, Gavin M. Davis, Claire E. McCoy, Glenn R. Bantug, David K. Finlay, Stephanie Annett, Jennifer K. Dowling, Chiara De Santi, Alex M. Liddicoat, Mariana P. Cervantes-Silva, Remsha Afzal, Peter J. Oefner, Linden J. Gearing, Dowling, Jennifer K [0000-0003-2842-1504], Afzal, Remsha [0000-0002-9023-6046], Gearing, Linden J [0000-0003-3508-3056], Dettmer, Katja [0000-0001-7337-2380], Gough, Daniel J [0000-0001-6479-1735], Bantug, Glenn R [0000-0003-2253-6028], Lavelle, Ed C [0000-0002-3167-1080], Finlay, David K [0000-0003-2716-6679], Robson, Tracy [0000-0003-4262-6872], Curtis, Annie M [0000-0002-9601-9624], Williams, Bryan RG [0000-0002-4969-1151], McCoy, Claire E [0000-0001-8710-896X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Science, Interleukin-1beta, 610 Medizin, General Physics and Astronomy, Down-Regulation, Inflammation, Oxidative phosphorylation, Mitochondrion, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, medicine, Animals, Acute inflammation, ARG2, Mice, Knockout, Phagocytes, ddc:610, Multidisciplinary, biology, Arginase, Chemistry, Succinate dehydrogenase, Macrophages, General Chemistry, Cell biology, Interleukin-10, Mitochondria, Mice, Inbred C57BL, Succinate Dehydrogenase, Interleukin 10, Metabolism, 030104 developmental biology, CNS, drug delivery, experimental autoimmune encephalomyelitis, inflammation, macrophage polarisation, microglia, microparticle, monocytes, multiple sclerosis, nanoparticle, biology.protein, Female, medicine.symptom, miRNA in immune cells, 030217 neurology & neurosurgery
Abstract: Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell., IL-10 can limit inflammation in part by inhibiting miR-155. Here the authors show how this axis induces mitochondrial arginase-2 to alter the mitochondrial dynamics and bioenergetics of macrophages and make these cells less pro-inflammatory.
Published: 2021

32. Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

Author: Caroline Saunders, Jeremy K. Nicholson, Nathalie Kingston, Lorinda Turner, John Bradley, Ian Goodfellow, Erik J M Toonen, Anne Elmer, Michael D Morgan, Michael P. Weekes, Berthold Göttgens, Paul A. Lyons, Paul J. Lehner, Aloka DeSa, Oisin Huhn, Myra Hosmillo, Kelvin Hunter, Nicholas J Matheson, Prasanti Kotagiri, Christoph Hess, James Thaventhiran, Pehuen Pereyra Gerber, Laura Bergamaschi, Anna M. Petrunkina, Ravindra K. Gupta, Benjamin J. Dunmore, Gordon Dougan, Aimee Hanson, Mark R. Wills, Kenneth G. C. Smith, Hélène Ruffieux, Sylvia Richardson, Federica Mescia, Fernando Calero Nieto, Rainer Doffinger, Stephen Baker, Mark Toshner, and CambridgeInstituteofTherapeuticImmunologyandInfectiousDisease-NationalInstituteofHealthResearch(CITI)
Subjects: Immune system, business.industry, Immunopathology, Immunology, medicine, Bystander effect, Inflammation, Tumor necrosis factor alpha, medicine.symptom, Systemic inflammation, business, Asymptomatic, Viral load
Abstract: SummaryIn a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust bystander CD8 T cell immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed bystander responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune defects may have clinical implications.
Published: 2021

33. Unlocking the potential of ordinary Portland cement with hydration control additive enabling low-carbon building materials

Author: Xuerun Li, Harald Grassl, Christoph Hesse, and Joachim Dengler
Subjects: Materials of engineering and construction. Mechanics of materials, TA401-492
Abstract: Abstract Ordinary Portland cement (OPC) is the core ingredient of many construction materials. In 2022, 4.1 billion tons were used worldwide, contributing to ~8% of CO2 emissions ( ~ 3 Gt/year). Nevertheless, the complete strength-generating capacity of OPC remains unrealized due to the restricted conversion of aluminates to ettringite, caused by conventional hydration kinetics. Here we show a hydration control additive that selectively modifies the hydration kinetics, thereby facilitating enhanced dissolution of aluminates (calcium aluminoferrite and tricalcium aluminate) in OPC, which promotes ettringite formation at a desired time. Increasing ettringite content improves packing of the hardened cement, resulting in ~50% higher specific strength and enabling cement reduction. It also increases OPC strength development efficiency, reducing carbon footprint by ~30%. The use of this additive can be combined with methods such as reducing water and/or using supplementary cementitious materials (SCMs) to prepare building materials with significantly fewer CO2 emissions than those from conventional OPC.
Published: 2024
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34. Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Author: Adrian J. Thrasher, J. Thaventheran, Austen Worth, Gašper Markelj, Christoph Hess, Alessia Cavazza, Mona Bajaj-Elliott, Michael Hollinshead, Rajeev Rai, Jonas Lötscher, Elizabeth Rivers, Rivers, Elizabeth [0000-0001-5814-8014], Worth, Austen [0000-0001-6803-7385], Thrasher, Adrian J [0000-0002-6097-6115], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, actin cytoskeleton, Mouse, Wiskott–Aldrich syndrome, Genetic enhancement, immunometabolism, Regulator, immunology, Immunology and Inflammation, 0302 clinical medicine, Homeostasis, Biology (General), Cytoskeleton, innate immune cells, 0303 health sciences, biology, General Neuroscience, Wiskott–Aldrich syndrome protein, General Medicine, Mitochondria, 3. Good health, Cell biology, Medicine, medicine.symptom, Wiskott-Aldrich Syndrome Protein, Research Article, Human, autophagy, QH301-705.5, Science, Wiskott Aldrich syndrome, Inflammation, macromolecular substances, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Immune system, medicine, Humans, Actin, 030304 developmental biology, General Immunology and Microbiology, Macrophages, Autophagy, Cell Biology, medicine.disease, Actin cytoskeleton, 030104 developmental biology, Gene Expression Regulation, inflammation, biology.protein, Flux (metabolism), 030217 neurology & neurosurgery
Abstract: The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.
Published: 2020

35. Author response: Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Author: Mona Bajaj-Elliott, Austen Worth, Gašper Markelj, Alessia Cavazza, James Thaventhiran, Jonas Lötscher, Elizabeth Rivers, Christoph Hess, Adrian J. Thrasher, Michael Hollinshead, and Rajeev Rai
Subjects: Selective autophagy, biology, Wiskott–Aldrich syndrome protein, Myeloid cells, biology.protein, Mitochondrial homeostasis, Cell biology
Published: 2020

36. The non-coding RNA miR-17~92 is a central mediator of T cell activation

Author: Christoph Hess, Lukas T. Jeker, Denis Seyres, Mara Kornete, Marianne Dölz, Julien Roux, Robin Kageyama, Romina Marone, Glenn R. Bantug, K. Mark Ansel, and John D. Gagnon
Subjects: Calcineurin, Transcriptome, medicine.anatomical_structure, NFAT Pathway, Transcription (biology), Chemistry, T cell, T-cell receptor, microRNA, medicine, CD28, Cell biology
Abstract: SummaryT cell activation is paramount for productive adaptive immune responses. CD28 is a key clinically targeted immunoregulatory receptor because it provides the prototypical costimulatory signal required for T cell activation. Therefore, a precise understanding of the molecular consequences of CD28 costimulation has direct therapeutic relevance. Here, we uncover that the microRNA cluster miR-17~92 is part of the molecular program triggered by CD28 costimulation and hence T cell activation. Combining genetics, transcriptomics, bioinformatics and biochemical miRNA:mRNA interaction maps we demonstrate that transgenic miR-17~92 can cell-intrinsically largely overcome defects caused by CD28-deficiency. miR-17~92 promotes transcription of a proinflammatory gene signature by enhancing the calcineurin/NFAT pathway. miR-17~92 binds to and represses a network of genes including several negative regulators of T cell activation. Finally, CD28-deficient T cells exhibit derepressed miR-17~92 target genes during activation, demonstrating that this non-coding RNA is required to shape the transcriptome. Thus, we propose that miR-17~92 constitutes a central mediator for T cell activation, integrating signals by the TCR and CD28 costimulation. In this model miR-17~92 facilitates T cell activation by dampening the breaks that prevent T cell activation.
Published: 2020

37. Reference Genes for Expression Studies in Human CD8+ Naïve and Effector Memory T Cells under Resting and Activating Conditions

Author: Gunhild Unterstab, Renato Paro, Marco Geigges, Christoph Hess, Patrick Gubser, Yannic Lecoultre, Geigges, Marco [0000-0001-9071-5162], Paro, Renato [0000-0003-3308-2965], and Apollo - University of Cambridge Repository
Subjects: Adult, CD4-Positive T-Lymphocytes, Male, Adolescent, T cell, Rest, SDHA, 38/90, lcsh:Medicine, Biology, CD8-Positive T-Lymphocytes, 13, Real-Time Polymerase Chain Reaction, law.invention, 38, Interferon-gamma, Young Adult, law, Reference genes, medicine, 631/250/1619/554/1834, Humans, RNA, Messenger, CD8-positive T cells, lcsh:Science, Polymerase chain reaction, Messenger RNA, Multidisciplinary, Effector, Gene Expression Profiling, lcsh:R, article, RNA, Reference Standards, Cell biology, 631/208/199, medicine.anatomical_structure, 631/1647/2017/2003, Reverse transcription polymerase chain reaction, 38/77, lcsh:Q, Female, Gene expression, Immunologic Memory, CD8
Abstract: Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) is widely used for mRNA quantification. To accurately measure changing gene transcript levels under different experimental conditions, the use of appropriate reference gene transcripts is instrumental. In T cell immunology, suitable reference genes have been reported for bulk CD4+ and CD8+ T cells. However, many CD4+ and CD8+ T cell subsets have been described in the past. Although they respond differently to given activation stimuli, proper validation of suitable reference genes in these subsets is lacking. In this study, we evaluated twelve commonly used reference gene products in human naïve (NV) and effector memory (EM) CD8+ T cells under non-activated and activated (2 h, 10 h and 20 h) conditions. We used five different statistical approaches for data analysis. Our results show that a number of widely used reference transcripts become differentially expressed under activating conditions. Using them as references markedly alters results as exemplified with IFNG mRNA expression. The only candidate reference gene products that remained stable during the activation process were 18S rRNA and SDHA mRNA, encouraging their usage as reference gene products for RT-qPCR experiments, when quantifying mRNA levels in human NV and EM CD8+ T cells., Scientific Reports, 10 (1), ISSN:2045-2322
Published: 2020

38. Early Immune Pathology and Persistent Dysregulation Characterise Severe COVID-19

Author: Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Helene Ruffieux, Aloka De Sa, Oisin Huhn, Mark R. Wills, Stephen Baker, Rainer Doffinger, Gordon Dougan, Anne Elmer, Ian Goodfellow, Ravindra K. Gupta, Myra Hosmillo, Kelvin Hunter, Nathalie Kingston, Paul Lehner, Nicholas J. Matheson, Jeremy K. Nicholson, Anna M. Petrunkina, Sylvia Richardson, Caroline Saunders, James Thaventhiran, Erik J. M. Toonen, Michael P. Weekes, (CITIID-NIHR) COVID BioResource Col Group, Mark Toshner, Christoph Hess, John R. Bradley, Paul A. Lyons, and Kenneth G.C. Smith
Subjects: medicine.medical_specialty, business.industry, Inflammation, Systemic inflammation, Asymptomatic, Clinical research, Immune system, Internal medicine, Immunopathology, Medicine, Tumor necrosis factor alpha, medicine.symptom, business, Viral load
Abstract: In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”. Funding: We are grateful for the generous support of CVC Capital Partners, the Evelyn Trust (20/75), UKRI COVID Immunology Consortium, Addenbrooke’s Charitable Trust (12/20A) and the NIHR Cambridge Biomedical Research Centre for their financial support. K.G.C.S. is the recipient of a Wellcome Investigator Award (200871/Z/16/Z); M.P.W. is the recipient of Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H. was funded by a Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M. was funded by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02); I.G.G. is a Wellcome Senior Fellow and was supported by funding from the Wellcome (Ref: 207498/Z/17/Z). Conflict of Interest: The authors declare they have no competing interests.
Published: 2020

39. Long-lived T follicular helper cells retain plasticity and help sustain humoral immunity

Author: Justin J. Taylor, Tamara C. Pereboom, Timm Maier, Christoph Hess, Ludivine C. Litzler, David Schreiner, Yusuf I. Ertuna, Nivedya Swarnalekha, Julien Roux, Carolyn G. King, Jonas Lötscher, Florian Geier, Roman P. Jakob, and Marco Künzli
Subjects: 0301 basic medicine, Programmed cell death, T cell, Immunology, Cell, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Immunity, medicine, Animals, PI3K/AKT/mTOR pathway, Mice, Knockout, Cell Death, Cell Differentiation, General Medicine, T-Lymphocytes, Helper-Inducer, Acquired immune system, NAD, Cell biology, Immunity, Humoral, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Humoral immunity, Receptors, Purinergic P2X7
Abstract: CD4; +; memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (T; cm; ) cells, whereas the existence and functional significance of long-lived T follicular helper (T; fh; ) cells are controversial. Here, we show that T; fh; cells are highly susceptible to NAD-induced cell death (NICD) during isolation from tissues, leading to their underrepresentation in prior studies. NICD blockade reveals the persistence of abundant T; fh; cells with high expression of hallmark T; fh; markers to at least 400 days after infection, by which time T; cm; cells are no longer found. Using single-cell RNA-seq, we demonstrate that long-lived T; fh; cells are transcriptionally distinct from T; cm; cells, maintain stemness and self-renewal gene expression, and, in contrast to T; cm; cells, are multipotent after recall. At the protein level, we show that folate receptor 4 (FR4) robustly discriminates long-lived T; fh; cells from T; cm; cells. Unexpectedly, long-lived T; fh; cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR-, HIF-1-, and cAMP-regulated genes. Late disruption of glycolysis/ICOS signaling leads to T; fh; cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of T; fh; and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct long-lived T cell subsets and establish T; fh; cells as an attractive target for the induction of durable adaptive immunity.
Published: 2020

40. Magnesium sensing via LFA-1 regulates CD8+ T cell effector function

Author: Jonas Lötscher, Adrià-Arnau Martí i Líndez, Nicole Kirchhammer, Elisabetta Cribioli, Greta Maria Paola Giordano Attianese, Marcel P. Trefny, Markus Lenz, Sacha I. Rothschild, Paolo Strati, Marco Künzli, Claudia Lotter, Susanne H. Schenk, Philippe Dehio, Jordan Löliger, Ludivine Litzler, David Schreiner, Victoria Koch, Nicolas Page, Dahye Lee, Jasmin Grählert, Dmitry Kuzmin, Anne-Valérie Burgener, Doron Merkler, Miklos Pless, Maria L. Balmer, Walter Reith, Jörg Huwyler, Melita Irving, Carolyn G. King, Alfred Zippelius, and Christoph Hess
Subjects: 610 Medicine & health, General Biochemistry, Genetics and Molecular Biology
Abstract: The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T��cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T��cells, enhanced effectiveness of bi-specific T��cell engaging antibodies, and improved CAR T��cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T��cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
Published: 2022

41. Early effector maturation of naïve human CD8+ T cells requires mitochondrial biogenesis

Author: Marco Fischer, Gunhild Unterstab, Jasmin Grählert, Ursula Sauder, Rebekah Steiner, Glenn R. Bantug, Christoph Hess, Patrick Gubser, Gideon Hoenger, Leyla Develioglu, Anne-Valérie Burgener, Sarah Dimeloe, and Maria L. Balmer
Subjects: 0301 basic medicine, Granzyme B production, biology, Cell division, Effector, T cell, Immunology, Cell biology, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Perforin, Mitochondrial biogenesis, biology.protein, medicine, Immunology and Allergy, Cytotoxic T cell, CD8
Abstract: The role of mitochondrial biogenesis during naive to effector differentiation of CD8+ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in supporting cytokine production of nascent activated human naive CD8+ T cells. Specifically, we found that prior to the first round of cell division activated naive CD8+ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter-linked and important for CD8+ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL-2 production - as well as subsequent IL-2 dependent TNF, IFN-γ, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8+ T cells.
Published: 2018

42. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade

Author: Viktor H. Koelzer, Didier Lardinois, Kirsten D. Mertz, Spasenija Savic Prince, Ping-Chih Ho, Jonathan C Hanhart, Daniela S. Thommen, Alfred Zippelius, Catherine Schill, Marcel P. Trefny, Vaios Karanikas, Sarah Dimeloe, Ton N. Schumacher, Mark Wiese, Andreas Roller, Petra Herzig, Christoph Hess, Christian Klein, Anna Kiialainen, University of Zurich, and Thommen, Daniela S
Subjects: 0301 basic medicine, Lung Neoplasms, Transcription, Genetic, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, 610 Medicine & health, Biology, CD8-Positive T-Lymphocytes, NSCLC, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, 1300 General Biochemistry, Genetics and Molecular Biology, T-Lymphocyte Subsets, 10049 Institute of Pathology and Molecular Pathology, Carcinoma, Non-Small-Cell Lung, medicine, Cytotoxic T cell, Humans, Lung cancer, T cell exhaustion, chemokine, General Medicine, T lymphocyte, Immunotherapy, CXCL13, immune checkpoint blockade, medicine.disease, Lipid Metabolism, Chemokine CXCL13, 3. Good health, Mitochondria, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Cytokine, medicine.anatomical_structure, Glucose, Phenotype, Virus Diseases, 030220 oncology & carcinogenesis, IL-10, Chronic Disease, Cancer research, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/ultrastructure, Carcinoma, Non-Small-Cell Lung/genetics, Carcinoma, Non-Small-Cell Lung/immunology, Chemokine CXCL13/metabolism, Glucose/metabolism, Lung Neoplasms/genetics, Lung Neoplasms/immunology, Lymphocytes, Tumor-Infiltrating/immunology, Mitochondria/metabolism, Mitochondria/ultrastructure, Programmed Cell Death 1 Receptor/metabolism, T-Lymphocyte Subsets/immunology, Virus Diseases/immunology, CD8
Abstract: Evidence from mouse chronic viral infection models suggests that CD8 + T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8 + T lymphocyte populations with high (PD-1 T ), intermediate (PD-1 N ) and no PD-1 expression (PD-1 - ) from non-small-cell lung cancer patients. PD-1 T T cells showed a markedly different transcriptional and metabolic profile from PD-1 N and PD-1 - lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1 T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1 T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
Published: 2018

43. Chronic inflammation and extracellular matrix-specific autoimmunity following inadvertent periarticular influenza vaccination

Author: Gideon Hoenger, Ivan Martin, Giorgio Tamborrini, Christoph Hess, Christoph Berger, Glenn R. Bantug, Arnaud Scherberich, Quan Zhen Li, Dorothee Harder, Mike Recher, Christian Marx, Thomas Daikeler, and Julia R. Hirsiger
Subjects: Adult, Male, T-Lymphocytes, T cell, Immunology, Osteoclasts, Autoimmunity, Inflammation, medicine.disease_cause, Young Adult, Immune system, Immunity, Influenza, Human, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Autoimmune disease, Receptor Activator of Nuclear Factor-kappa B, Tartrate-Resistant Acid Phosphatase, business.industry, Histocompatibility Testing, Vaccination, Orthomyxoviridae, medicine.disease, Extracellular Matrix, medicine.anatomical_structure, Influenza Vaccines, Rheumatoid arthritis, Chronic Disease, Female, medicine.symptom, business, Heparan Sulfate Proteoglycans, Joint Capsule, HLA-DRB1 Chains
Abstract: Background Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage (‘shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. Methods We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. Findings Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. Conclusion Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.
Published: 2021

44. Unraveling the Mechanism and Kinetics of Binding of an LCI‐eGFP‐Polymer for Antifouling Coatings

Author: Felix Jakob, Khosrow Rahimi, Manuela Garay-Sarmiento, Fabian Obstals, Mehdi D. Davari, Sarah Dedisch, Tamás Haraszti, Cesar Rodriguez-Emmenegger, Christoph Heß, Ulrich Schwaneberg, and Dominik Söder
Subjects: Polymers and Plastics, Biofouling, Polymers, Surface Properties, Radical polymerization, Bioengineering, 02 engineering and technology, Degree of polymerization, 010402 general chemistry, 01 natural sciences, Polymerization, Biomaterials, Adsorption, ddc:570, Materials Chemistry, chemistry.chemical_classification, Chemistry, Polymer, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Kinetics, Chemical engineering, Surface modification, 0210 nano-technology, Biotechnology, Macromolecule
Abstract: Macromolecular bioscience 2100158 (2021). doi:10.1002/mabi.202100158 special issue: "Hot Topic: Surfaces and Interfaces", Published by Wiley-VCH, Weinheim
Published: 2021

45. Detection of Sp110 by Flow Cytometry and Application to Screening Patients for Veno-occlusive Disease with Immunodeficiency

Author: Rabi Hanna, Alexander A. Navarini, Janet Chou, Marc B. Bigler, Joeseph A. Church, Christoph Berger, Luigi D. Notarangelo, Polina Stepensky, Anne Valérie Burgener, Fariba Rezaee, Fabian Baldin, Mike Recher, Rebecca Higgins, Waleed Al-Herz, Florian Marquardsen, Gérard Lefranc, Shlomit Kfir-Erenfeld, Christoph Hess, Raif S. Geha, Benedikt J. Meyer, Florian Wunderer, Raymond Mikhael, Zeina Baz, Daniel Bloch, and Annaïse Jauch
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, T-Lymphocytes, Immunology, Hepatic Veno-Occlusive Disease, Disease, Biology, Article, Adenoviridae, Minor Histocompatibility Antigens, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Medical microbiology, Cell Line, Tumor, medicine, Humans, Immunology and Allergy, Child, Immunodeficiency, Sanger sequencing, Severe combined immunodeficiency, Newborn screening, T-cell receptor excision circles, Immunologic Deficiency Syndromes, Nuclear Proteins, Flow Cytometry, medicine.disease, 3. Good health, 030104 developmental biology, 13. Climate action, Child, Preschool, Leukocytes, Mononuclear, symbols, Primary immunodeficiency, Female, 030217 neurology & neurosurgery
Abstract: Mutations in Sp110 are the underlying cause of veno-occlusive disease with immunodeficiency (VODI), a combined immunodeficiency that is difficult to treat and often fatal. Because early treatment is critically important for patients with VODI, broadly usable diagnostic tools are needed to detect Sp110 protein deficiency. Several factors make establishing the diagnosis of VODI challenging: (1) Current screening strategies to identify severe combined immunodeficiency are based on measuring T cell receptor excision circles (TREC). This approach will fail to identify VODI patients because the disease is not associated with severe T cell lymphopenia at birth; (2) the SP110 gene contains 17 exons, making it a challenge for Sanger sequencing. The recently developed next-generation sequencing (NGS) platforms that can rapidly determine the sequence of all 17 exons are available in only a few laboratories; (3) there is no standard functional assay to test for the effects of novel mutations in Sp110; and (4) it has been difficult to use flow cytometry to identify patients who lack Sp110 because of the low level of Sp110 protein in peripheral blood lymphocytes. We report here a novel flow cytometric assay that is easily performed in diagnostic laboratories and might thus become a standard assay for the evaluation of patients who may have VODI. In addition, the assay will facilitate investigations directed at understanding the function of Sp110.
Published: 2017

46. Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis

Author: Raphael Jeker, Rebecca Higgins, Thomas Daikeler, Olivier Bignucolo, Anne-Valérie Burgener, Annemarie Gabrysch, Benedikt J. Meyer, Annaïse Jauch, Christoph Hess, Jan-Olaf Gebbers, Matthias Mehling, Alexander A. Navarini, Fabian Baldin, Bodo Grimbacher, Charlotte Schwab, Anne Kistner, Petr Hruz, Fabian Meienberg, Ingmar Heijnen, Barbara-Christina Padberg Sgier, Florian Marquardsen, David M. Sansom, Lukas T. Jeker, Marc B. Bigler, Olle Kämpe, Mike Recher, Christoph Berger, Natalie Frede, and Tie Zheng Hou
Subjects: 0301 basic medicine, Enterocolitis, biology, business.industry, Immunology, Vedolizumab, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, CTLA-4, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Monoclonal, medicine, biology.protein, Immunology and Allergy, Missense mutation, Antibody, medicine.symptom, business, medicine.drug
Published: 2017
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47. JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms

Author: Sarah Dimeloe, Max Gassmann, Vladan P. Čokić, Florian Geier, Julien Delezie, Julia Magdalena Majewska, Teresa Cassel, Jonel Trebicka, Thomas Radimerski, Deniz Gezer, Christoph Handschin, Nils Hansen, Radek C. Skoda, Shivam Rai, Danijela Lekovic, Dominik Wolf, Ronny Nienhold, Hui Hao-Shen, Nicolaus Kröger, Serena Di Palma, Steffen Koschmieder, Serena Galli, Andrew N. Lane, Stefan Dirnhofer, Christian Beisel, Julian Hilfiker, Teresa W.-M. Fan, Christoph Hess, Nicola Andina, Tata Nageswara Rao, University of Zurich, and Skoda, Radek C
Subjects: 0301 basic medicine, 1303 Biochemistry, Immunology, 2720 Hematology, 10071 Functional Genomics Center Zurich, Oxidative phosphorylation, Biology, Biochemistry, Transcriptome, Pathogenesis, 1307 Cell Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Humans, Glycolysis, Progenitor cell, 2403 Immunology, Myeloproliferative Disorders, Cell Biology, Hematology, Janus Kinase 2, 10081 Institute of Veterinary Physiology, Hematopoietic Stem Cells, 3. Good health, Haematopoiesis, 030104 developmental biology, 030220 oncology & carcinogenesis, 10076 Center for Integrative Human Physiology, Cancer cell, Mutation, Cancer research, Erythropoiesis, 570 Life sciences, biology
Abstract: Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
Published: 2019

48. Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4

Author: Patrick Gubser, Corina Frick, Sarah Dimeloe, Yannic Lecoultre, Alfred Zippelius, Anja Langenkamp, Glenn R. Bantug, Leyla Develioglu, Daniela S. Thommen, Jordan Loeliger, Marco Fischer, Christoph Hess, and Florian Marquardsen
Subjects: CD4-Positive T-Lymphocytes, medicine.medical_treatment, T cell, Cell, Smad Proteins, SMAD, Mitochondrion, Biochemistry, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Adenosine Triphosphate, Oxygen Consumption, Interferon, Transforming Growth Factor beta, Neoplasms, medicine, Tumor Microenvironment, Animals, Humans, Phosphorylation, Molecular Biology, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Chemistry, Cell Biology, Mitochondrial Proton-Translocating ATPases, 3. Good health, Cell biology, Mitochondria, medicine.anatomical_structure, Cytokine, 030220 oncology & carcinogenesis, Signal transduction, medicine.drug, Signal Transduction
Abstract: Transforming growth factor-β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β-mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type-specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.
Published: 2019

49. Memory CD8

Author: Maria L, Balmer, Eric H, Ma, Andrew J, Thompson, Raja, Epple, Gunhild, Unterstab, Jonas, Lötscher, Philippe, Dehio, Christian M, Schürch, Jan D, Warncke, Gaëlle, Perrin, Anne-Kathrin, Woischnig, Jasmin, Grählert, Jordan, Löliger, Nadine, Assmann, Glenn R, Bantug, Olivier P, Schären, Nina, Khanna, Adrian, Egli, Lukas, Bubendorf, Katharina, Rentsch, Siegfried, Hapfelmeier, Russell G, Jones, and Christoph, Hess
Subjects: Male, Mice, Inbred C57BL, Mice, Anti-Inflammatory Agents, Animals, Humans, Female, Acetates, CD8-Positive T-Lymphocytes
Abstract: Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8
Published: 2019

50. Protection of bona fide T follicular memory cells during tissue isolation reveals their persistence, plasticity and functional impact

Author: Florian Geier, Nivedya Swarnalekha, J. T. Taylor, Carolyn G. King, Marco Künzli, Jonas Lötscher, David Schreiner, Tamara C. Pereboom, Julien Roux, Yusuf I. Ertuna, and Christoph Hess
Subjects: medicine.anatomical_structure, Immune system, Antigen, Memory cell, Effector, Cell, medicine, Biology, Gene, Phenotype, PI3K/AKT/mTOR pathway, Cell biology
Abstract: SUMMARYCD4 memory T cells play an important role in protective immunity and are a key target in vaccine development. Many studies have focused on T central memory (TCM) cells, while the existence and functional significance of T follicular helper (TFH) memory cells is controversial. Here we show that TFH memory cells are highly susceptible to NAD induced cell death (NICD) during isolation from tissues, leading to their under-representation in prior studies. NICD blockade reveals the persistence of abundant TFH memory cells, with high expression of hallmark TFH markers, that persist to at least 400 days after infection, by which time TCM cells are no longer found. Using single cell RNA-seq we demonstrate that TFH memory cells are transcriptionally distinct from TCM cells, maintain stemness and self-renewal gene expression, and, in contrast to TCM cells, are multipotent following recall. Surprisingly, TFH memory cells concurrently express a distinct glycolytic signature similar to trained immune cells, including elevated expression of mTOR, HIF-1 and cAMP regulated genes. Late disruption of glycolysis/ICOS signaling leads to TFH memory cell depletion concomitant with decreased splenic plasma cells and circulating antibody titers, demonstrating both unique homeostatic regulation of memory TFH and their sustained function during the memory phase of the immune response. These results highlight the metabolic heterogeneity underlying distinct memory T cell subsets and establish TFH memory cells as an attractive target for the induction of long-lived adaptive immunity.HIGHLIGHTSCell death during isolation from the tissue prevents the full recovery of TFH memory cellsTFH memory cells are transcriptionally distinct from TCM cells and maintain a broader recall capacityTFH memory cells are maintained in the absence of antigen but require ICOS signaling and glycolysisTFH memory cells support late phase antibody production by splenic plasma cells
Published: 2019

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