23 results on '"Van Der Heide V"'
Search Results
2. Akutes nichtallergisches Angioödem
- Author
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van der Heide, V., primary, Woehrle, T., additional, Ripperger, M., additional, and Huge, V., additional
- Published
- 2015
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3. Universal recording of immune cell interactions in vivo.
- Author
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Nakandakari-Higa S, Walker S, Canesso MCC, van der Heide V, Chudnovskiy A, Kim DY, Jacobsen JT, Parsa R, Bilanovic J, Parigi SM, Fiedorczuk K, Fuchs E, Bilate AM, Pasqual G, Mucida D, Kamphorst AO, Pritykin Y, and Victora GD
- Subjects
- Ligands, Germinal Center cytology, Single-Cell Gene Expression Analysis, Intestinal Mucosa cytology, Intestinal Mucosa immunology, Lymphocytic choriomeningitis virus immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis virology, Organ Specificity, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Communication immunology, Dendritic Cells cytology, Dendritic Cells immunology, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, T Follicular Helper Cells cytology, T Follicular Helper Cells immunology, B-Lymphocytes cytology, B-Lymphocytes immunology, Epithelial Cells cytology, Epithelial Cells immunology
- Abstract
Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function
1 . To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)2 , an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8+ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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4. Functional impairment of "helpless" CD8 + memory T cells is transient and driven by prolonged but finite cognate antigen presentation.
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van der Heide V, Davenport B, Cubitt B, Roudko V, Choo D, Humblin E, Jhun K, Angeliadis K, Dawson T, Furtado G, Kamphorst A, Ahmed R, de la Torre JC, and Homann D
- Abstract
Generation of functional CD8
+ T cell memory typically requires engagement of CD4+ T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (TE ) and subsequent memory (TM ) CD8+ T cell formation appear impervious to a lack of CD4+ T cell help during priming. Nonetheless, such "helpless" CD8+ TM respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8+ T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8+ TE differentiation is largely normal but a multiplicity of helpless CD8 TM defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8+ TM potential and recall capacity. Our findings provide a unified explanation for helpless CD8+ T cell memory and emphasize an unexpected CD8+ TM plasticity with implications for vaccination strategies and beyond.- Published
- 2024
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5. Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1 + PD-1 + CD8 T cells.
- Author
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Humblin E, Korpas I, Lu J, Filipescu D, van der Heide V, Goldstein S, Vaidya A, Soares-Schanoski A, Casati B, Selvan ME, Gümüş ZH, Wieland A, Corrado M, Cohen-Gould L, Bernstein E, Homann D, Chipuk J, and Kamphorst AO
- Subjects
- Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Cell Differentiation, Transcription Factors, T Cell Transcription Factor 1 genetics, CD28 Antigens
- Abstract
During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1
+ ) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.- Published
- 2023
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6. Advancing beyond the twists and turns of T cell exhaustion in cancer.
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van der Heide V, Humblin E, Vaidya A, and Kamphorst AO
- Subjects
- Humans, Lymphocyte Activation, Tumor Microenvironment, Cell Differentiation, CD8-Positive T-Lymphocytes, Neoplasms
- Abstract
Chronic antigen stimulation leads to T cell exhaustion. Nutrient restrictions and other suppressive factors in the tumor microenvironment further exacerbate T cell dysfunction. Better understanding of heterogeneity and dynamics of exhausted CD8 T cells will guide novel therapies that modulate T cell differentiation to achieve more effective antitumor responses.
- Published
- 2022
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7. Limited extent and consequences of pancreatic SARS-CoV-2 infection.
- Author
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van der Heide V, Jangra S, Cohen P, Rathnasinghe R, Aslam S, Aydillo T, Geanon D, Handler D, Kelley G, Lee B, Rahman A, Dawson T, Qi J, D'Souza D, Kim-Schulze S, Panzer JK, Caicedo A, Kusmartseva I, Posgai AL, Atkinson MA, Albrecht RA, García-Sastre A, Rosenberg BR, Schotsaert M, and Homann D
- Subjects
- Humans, Pancreas, SARS-CoV-2, COVID-19, Diabetes Mellitus, Insulin-Secreting Cells
- Abstract
Concerns that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may cause new-onset diabetes persist in an evolving research landscape, and precise risk assessment is hampered by, at times, conflicting evidence. Here, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, we demonstrate that productive infection is strictly dependent on the SARS-CoV-2 entry receptor ACE2 and targets practically all pancreatic cell types. Importantly, the infection remains highly circumscribed and largely non-cytopathic and, despite a high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with endemic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, challenge the proposition that in vivo targeting of β cells by SARS-CoV-2 precipitates new-onset diabetes. Whether restricted pancreatic damage and immunological alterations accrued by COVID-19 increase cumulative diabetes risk, however, remains to be evaluated., Competing Interests: Declaration of interests The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, and Merck outside of the reported work. A.G.-S. has consulting agreements outside of the reported work for the following companies, involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, and Pfizer. A.G.-S. is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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8. Expression of SARS-CoV-2 Entry Factors in the Pancreas of Normal Organ Donors and Individuals with COVID-19.
- Author
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Kusmartseva I, Wu W, Syed F, Van Der Heide V, Jorgensen M, Joseph P, Tang X, Candelario-Jalil E, Yang C, Nick H, Harbert JL, Posgai AL, Paulsen JD, Lloyd R, Cechin S, Pugliese A, Campbell-Thompson M, Vander Heide RS, Evans-Molina C, Homann D, and Atkinson MA
- Subjects
- Angiotensin-Converting Enzyme 2 analysis, Angiotensin-Converting Enzyme 2 metabolism, COVID-19 complications, COVID-19 metabolism, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Gene Expression, Humans, Pancreas blood supply, Serine Endopeptidases analysis, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Tissue Donors, Angiotensin-Converting Enzyme 2 genetics, COVID-19 genetics, Pancreas metabolism, SARS-CoV-2 physiology, Virus Internalization
- Abstract
Diabetes is associated with increased mortality from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Given literature suggesting a potential association between SARS-CoV-2 infection and diabetes induction, we examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2), the key entry factor for SARS-CoV-2 infection. Specifically, we analyzed five public scRNA-seq pancreas datasets and performed fluorescence in situ hybridization, western blotting, and immunolocalization for ACE2 with extensive reagent validation on normal human pancreatic tissues across the lifespan, as well as those from coronavirus disease 2019 (COVID-19) cases. These in silico and ex vivo analyses demonstrated prominent expression of ACE2 in pancreatic ductal epithelium and microvasculature, but we found rare endocrine cell expression at the mRNA level. Pancreata from individuals with COVID-19 demonstrated multiple thrombotic lesions with SARS-CoV-2 nucleocapsid protein expression that was primarily limited to ducts. These results suggest SARS-CoV-2 infection of pancreatic endocrine cells, via ACE2, is an unlikely central pathogenic feature of COVID-19-related diabetes., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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9. Chemokine Signatures of Pathogen-Specific T Cells I: Effector T Cells.
- Author
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Eberlein J, Davenport B, Nguyen TT, Victorino F, Jhun K, van der Heide V, Kuleshov M, Ma'ayan A, Kedl R, and Homann D
- Subjects
- Animals, Chemokines genetics, Infections genetics, Mice, Mice, Inbred BALB C, Mice, Knockout, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Chemokines immunology, Infections immunology
- Abstract
The choreography of complex immune responses, including the priming, differentiation, and modulation of specific effector T cell populations generated in the immediate wake of an acute pathogen challenge, is in part controlled by chemokines, a large family of mostly secreted molecules involved in chemotaxis and other patho/physiological processes. T cells are both responsive to various chemokine cues and a relevant source for certain chemokines themselves; yet, the actual range, regulation, and role of effector T cell-derived chemokines remains incompletely understood. In this study, using different in vivo mouse models of viral and bacterial infection as well as protective vaccination, we have defined the entire spectrum of chemokines produced by pathogen-specific CD8
+ and CD4+ T effector cells and delineated several unique properties pertaining to the temporospatial organization of chemokine expression patterns, synthesis and secretion kinetics, and cooperative regulation. Collectively, our results position the "T cell chemokine response" as a notably prominent, largely invariant, yet distinctive force at the forefront of pathogen-specific effector T cell activities and establish novel practical and conceptual approaches that may serve as a foundation for future investigations into the role of T cell-produced chemokines in infectious and other diseases., (Copyright © 2020 by The American Association of Immunologists, Inc.)- Published
- 2020
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10. Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection.
- Author
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Davenport B, Eberlein J, Nguyen TT, Victorino F, van der Heide V, Kuleshov M, Ma'ayan A, Kedl R, and Homann D
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- Acute Disease, Animals, Chemokines genetics, Chronic Disease, Infections genetics, Mice, Mice, Inbred BALB C, Mice, Knockout, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Chemokines immunology, Immunologic Memory, Infections immunology
- Abstract
Pathogen-specific memory T cells (T
M ) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning. An integrated perspective, however, needs to consider TM as a potentially relevant chemokine source themselves. In this study, we employed a comprehensive transcriptional/translational profiling strategy to delineate the identities, expression patterns, and dynamic regulation of chemokines produced by murine pathogen-specific TM CD8+ TM , and to a lesser extent CD4+ TM , are a prodigious source for six select chemokines (CCL1/3/4/5, CCL9/10, and XCL1) that collectively constitute a prominent and largely invariant signature across acute and chronic infections. Notably, constitutive CCL5 expression by CD8+ TM serves as a unique functional imprint of prior antigenic experience; induced CCL1 production identifies highly polyfunctional CD8+ and CD4+ TM subsets; long-term CD8+ TM maintenance is associated with a pronounced increase of XCL1 production capacity; chemokines dominate the earliest stages of the CD8+ TM recall response because of expeditious synthesis/secretion kinetics (CCL3/4/5) and low activation thresholds (CCL1/3/4/5/XCL1); and TM chemokine profiles modulated by persisting viral Ags exhibit both discrete functional deficits and a notable surplus. Nevertheless, recall responses and partial virus control in chronic infection appear little affected by the absence of major TM chemokines. Although specific contributions of TM -derived chemokines to enhanced immune protection therefore remain to be elucidated in other experimental scenarios, the ready visualization of TM chemokine-expression patterns permits a detailed stratification of TM functionalities that may be correlated with differentiation status, protective capacities, and potential fates., (Copyright © 2020 by The American Association of Immunologists, Inc.)- Published
- 2020
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11. Shared CD8 + T cell receptors for SARS-CoV-2.
- Author
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Levantovsky R and van der Heide V
- Published
- 2020
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12. Lentiviral-Vector-Based Dendritic Cell Vaccine Synergizes with Checkpoint Blockade to Clear Chronic Viral Infection.
- Author
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Norton TD, Tada T, Leibowitz R, van der Heide V, Homann D, and Landau NR
- Subjects
- Animals, Biomarkers, Dendritic Cells virology, Disease Models, Animal, Disease Susceptibility, Histocompatibility Antigens Class II, Host-Pathogen Interactions immunology, Humans, Lymphocytic Choriomeningitis prevention & control, Lymphocytic choriomeningitis virus immunology, Mice, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Viral Vaccines administration & dosage, Virus Diseases etiology, Virus Diseases immunology, Dendritic Cells drug effects, Dendritic Cells immunology, Genetic Vectors administration & dosage, Genetic Vectors genetics, Immune Checkpoint Inhibitors pharmacology, Lentivirus genetics, Viral Vaccines immunology, Virus Diseases prevention & control
- Abstract
Dendritic cell vaccines are a promising strategy for the treatment of cancer and infectious diseases but have met with mixed success. We report on a lentiviral vector-based dendritic cell vaccine strategy that generates a cluster of differentiation 8 (CD8) T cell response that is much stronger than that achieved by standard peptide-pulsing approaches. The strategy was tested in the mouse lymphocytic choriomeningitis virus (LCMV) model. Bone marrow-derived dendritic cells from SAMHD1 knockout mice were transduced with a lentiviral vector expressing the GP33 major-histocompatibility-complex (MHC)-class-I-restricted peptide epitope and CD40 ligand (CD40L) and injected into wild-type mice. The mice were highly protected against acute and chronic variant CL-13 LCMVs, resulting in a 100-fold greater decrease than that achieved with peptide epitope-pulsed dendritic cells. Inclusion of an MHC-class-II-restricted epitope in the lentiviral vector further increased the CD8 T cell response and resulted in antigen-specific CD8 T cells that exhibited a phenotype associated with functional cytotoxic T cells. The vaccination synergized with checkpoint blockade to reduce the viral load of mice chronically infected with CL-13 to an undetectable level. The strategy improves upon current dendritic cell vaccine strategies; is applicable to the treatment of disease, including AIDS and cancer; and supports the utility of Vpx-containing vectors., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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13. Innate T cells in COVID-19: friend or foe?
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van der Heide V
- Published
- 2020
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14. SARS-CoV-2 cross-reactivity in healthy donors.
- Author
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van der Heide V
- Published
- 2020
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15. Immunology of COVID-19: Current State of the Science.
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Vabret N, Britton GJ, Gruber C, Hegde S, Kim J, Kuksin M, Levantovsky R, Malle L, Moreira A, Park MD, Pia L, Risson E, Saffern M, Salomé B, Esai Selvan M, Spindler MP, Tan J, van der Heide V, Gregory JK, Alexandropoulos K, Bhardwaj N, Brown BD, Greenbaum B, Gümüş ZH, Homann D, Horowitz A, Kamphorst AO, Curotto de Lafaille MA, Mehandru S, Merad M, and Samstein RM
- Subjects
- Animals, COVID-19, Coronavirus Infections diagnosis, Coronavirus Infections pathology, Coronavirus Infections therapy, Disease Susceptibility, Humans, Immunity, Innate, Immunologic Memory, Inflammation immunology, Inflammation virology, Lymphocytes immunology, Myeloid Cells immunology, Pandemics, Pneumonia, Viral diagnosis, Pneumonia, Viral pathology, Pneumonia, Viral therapy, SARS-CoV-2, Betacoronavirus physiology, Coronavirus Infections immunology, Pneumonia, Viral immunology
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection., Competing Interests: Declaration of Interests N.B. serves as an advisor/board member for Neon, Checkpoint Sciences, Primevax, Novartis, Array BioPharma, Roche, Avidea, Boeringer Ingelheim, Rome Therapeutics, Roswell Park, and the Parker Institute for Cancer Immunotherapy. N.B. receives research support from the Parker Insitute, Novocure, Celldex, Genentech, Oncovir, and Regeneron. M.M. serves as an advisor/board member for Celsius, Pionyr, Compugen, Myeloids and Innate pharma and ad hoc for Takeda. M.M. receives research support from Regeneron, Takeda, and Genentech. A.M. has equity in Gilead Sciences and Regeneron Pharmaceuticals., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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16. Neutralizing antibody response in mild COVID-19.
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van der Heide V
- Published
- 2020
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17. Aging boosts antiviral CD8+T cell memory through improved engagement of diversified recall response determinants.
- Author
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Davenport B, Eberlein J, Nguyen TT, Victorino F, Jhun K, Abuirqeba H, van der Heide V, Heeger P, and Homann D
- Subjects
- Animals, Arenaviridae Infections virology, Cytokines metabolism, Gene Expression Regulation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Aging immunology, Arenaviridae Infections immunology, CD8-Positive T-Lymphocytes immunology, Cytokines immunology, Immunologic Memory immunology, Lymphocytic choriomeningitis virus immunology, Mental Recall physiology
- Abstract
The determinants of protective CD8+ memory T cell (CD8+TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8+TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8+TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8+TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8+T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8+TM properties are gradually aligned with those of naïve CD8+T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8+TM immunity., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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18. Aging of Antiviral CD8 + Memory T Cells Fosters Increased Survival, Metabolic Adaptations, and Lymphoid Tissue Homing.
- Author
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Davenport B, Eberlein J, van der Heide V, Jhun K, Nguyen TT, Victorino F, Trotta A, Chipuk J, Yi Z, Zhang W, Clambey ET, Scott DK, and Homann D
- Subjects
- Animals, Antigens, Viral immunology, Cell Movement, Cell Survival, Cells, Cultured, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Antigen, T-Cell genetics, Aging immunology, CD8-Positive T-Lymphocytes physiology, Immunologic Memory immunology, Lymph Nodes immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus physiology
- Abstract
Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8
+ T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (TM ) homeostasis. Over time, CD8+ TM generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+ TM quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+ TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+ TM accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+ TM poised for greater recall responses., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
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19. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis.
- Author
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Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, Kalinovich AV, Petrovic N, Wolf Y, Clemmensen C, Shin AC, Divanovic S, Brombacher F, Glasmacher E, Keipert S, Jastroch M, Nagler J, Schramm KW, Medrikova D, Collden G, Woods SC, Herzig S, Homann D, Jung S, Nedergaard J, Cannon B, Tschöp MH, Müller TD, and Buettner C
- Subjects
- Adaptation, Physiological, Adipocytes drug effects, Adipose Tissue drug effects, Adipose Tissue, Brown drug effects, Adipose Tissue, Brown metabolism, Adipose Tissue, White drug effects, Adipose Tissue, White metabolism, Animals, Blotting, Western, Body Composition immunology, Catecholamines metabolism, Cell Differentiation, Culture Media, Conditioned, Energy Metabolism genetics, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Interleukin-4 immunology, Interleukin-4 pharmacology, Macrophages drug effects, Mice, Mice, Knockout, Receptors, Cell Surface genetics, Thermogenesis genetics, Uncoupling Protein 1 genetics, Adipocytes metabolism, Adipose Tissue metabolism, Macrophages immunology, Norepinephrine metabolism, Receptors, Adrenergic, beta-3 metabolism, Thermogenesis immunology, Tyrosine 3-Monooxygenase genetics
- Abstract
Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1
-/- and interleukin-4 receptor-α double-negative (Il4ra-/- ) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.- Published
- 2017
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20. CD28 days later: Resurrecting costimulation for CD8(+) memory T cells.
- Author
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van der Heide V and Homann D
- Subjects
- Animals, B7-1 Antigen genetics, CD8-Positive T-Lymphocytes immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Signal Transduction immunology, CD28 Antigens genetics, Immunologic Memory genetics
- Abstract
Rapid activation and proliferative expansion of specific CD8(+) memory T (CD8(+) TM ) cells upon antigen re-encounter is a critical component of the adaptive immune response that confers enhanced immune protection. In this context, however, the requirements for costimulation in general, and CD28 signaling in particular, remain incompletely defined. In the current issue of the European Journal of Immunology, Fröhlich et al. [Eur. J. Immunol. 2016. 46: 1644-1655] provide definitive evidence that optimal elaboration of CD8(+) TM -cell recall responses is indeed contingent on CD28 expressed by these cells. Here, we discuss the "CD28 costimulation paradigm" in its historical context and highlight some of the unresolved complexities pertaining to CD28-dependent interactions that shape CD8(+) T-cell phenotypes, functionalities, and recall reactivity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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21. Down-regulation of MicroRNA-31 in CD4+ T Cells Contributes to Immunosuppression in Human Sepsis by Promoting TH2 Skewing.
- Author
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van der Heide V, Möhnle P, Rink J, Briegel J, and Kreth S
- Subjects
- Adult, Blotting, Western, Cells, Cultured, Female, Flow Cytometry, Humans, Male, Middle Aged, Real-Time Polymerase Chain Reaction, CD4-Positive T-Lymphocytes immunology, Down-Regulation immunology, Immune Tolerance immunology, MicroRNAs immunology, Sepsis immunology, Th2 Cells immunology
- Abstract
Background: Immunosuppression has been recognized as a major cause of sepsis-related mortality. Currently, there is much interest in identifying central hubs controlling septic immunoparalysis. In this context, in this study, the authors investigate the role of microRNA-31 (miR-31) as a regulator of T cell functions., Methods: Primary human T cells were separated from healthy volunteers (n = 16) and from sepsis patients by magnetic beads (n = 23). Expression of mRNA/microRNA (miRNA) was determined by real-time polymerase chain reaction. Gene silencing was performed by small interfering RNA transfection, and miRNA-binding sites were validated by reporter gene assays. Effects of miR-31 or anti-miR-31 transfection were analyzed by real-time polymerase chain reaction, Western blotting, and flow cytometry., Results: Overexpression of miR-31 in stimulated CD4 T cells promoted a proinflammatory phenotype with increased levels of interferon-γ (1.63 ± 0.43; P = 0.001; means ± SD) and reduced expression of interleukin (IL)-2 (0.66 ± 0.19; P = 0.005) and IL-4 (0.80 ± 0.2; P = 0.0001). In contrast, transfection of anti-miR-31 directed cells toward a TH2 phenotype. Effects on IL-2 and IL-4 were mediated by targeting of nuclear factor-kappa B-inducing kinase and factor-inhibiting hypoxia-inducible factor-1α. Interferon-γ, however, was influenced via control of signaling lymphocytic activation molecule (SLAM)-associated protein, an essential adaptor molecule of immunomodulatory SLAM receptor signaling, which was identified as a novel target gene of miR-31. In sepsis patients, an epigenetically driven down-regulation of miR-31 was found (0.44 ± 0.25; P = 0.0001), associated with increased nuclear factor-kappa B-inducing kinase, factor-inhibiting hypoxia-inducible factor-1α, SLAM-associated protein expression, and a cytokine shift toward TH2., Conclusions: In this study, the authors provide novel evidence of miR-31 as an emerging key posttranscriptional regulator of sepsis-associated immunosuppression. The study results contribute to a further understanding of septic immunoparalysis and provide new perspectives on miRNA-based diagnostic approaches.
- Published
- 2016
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22. MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKCε.
- Author
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Möhnle P, Schütz SV, van der Heide V, Hübner M, Luchting B, Sedlbauer J, Limbeck E, Hinske LC, Briegel J, and Kreth S
- Subjects
- Cell Differentiation, Gene Expression Regulation, Humans, MicroRNAs immunology, Phosphorylation, Primary Cell Culture, Protein Kinase C-epsilon immunology, STAT4 Transcription Factor immunology, Sepsis immunology, Sepsis pathology, Signal Transduction, Th1 Cells pathology, MicroRNAs genetics, Protein Kinase C-epsilon genetics, STAT4 Transcription Factor genetics, Sepsis genetics, Th1 Cells immunology
- Abstract
T-cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA-146a (miR-146a) has been identified as a key negative regulator of T-cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR-146a-driven pathways in primary human T cells. Our results identify miR-146a as a critical gatekeeper of Th1-cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR-146a targets protein kinase C epsilon (PRKCε), which is part of a functional complex consisting of PRKCε and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKCε phosphorylates STAT4, which in turn is capable of promoting Th1-cell differentiation processes in human CD4(+) T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR-146a and an increased PRKCε expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR-146a as a potent inhibitor of Th1-cell differentiation in human T cells and suggest that dysregulation of miR-146a contributes to the pathogenesis of sepsis., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
- View/download PDF
23. Chronic granulomatous disease in an adult recognized by an invasive aspergillosis.
- Author
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Kaufmann I, Briegel J, van der Heide V, Chouker A, Frey L, Spiekermann K, Mayr D, and Thiel M
- Subjects
- Aspergillus drug effects, Diagnosis, Differential, Germany, Granulomatous Disease, Chronic genetics, Humans, Infusions, Parenteral, Invasive Pulmonary Aspergillosis diagnosis, Invasive Pulmonary Aspergillosis pathology, Itraconazole therapeutic use, Lung drug effects, Lung pathology, Lung surgery, Male, Membrane Glycoproteins genetics, NADPH Oxidase 2, NADPH Oxidases genetics, Phagocytes chemistry, Pyrimidines therapeutic use, Respiratory Insufficiency physiopathology, Tachypnea physiopathology, Treatment Outcome, Triazoles therapeutic use, Voriconazole, Young Adult, Antifungal Agents therapeutic use, Aspergillus isolation & purification, Granulomatous Disease, Chronic complications, Granulomatous Disease, Chronic diagnosis, Invasive Pulmonary Aspergillosis microbiology, Invasive Pulmonary Aspergillosis therapy, Respiratory Insufficiency therapy
- Abstract
A 20-year-old man without any history of a pulmonary disease presented initially with a 1-day history of fever and tachypnea and developed an acute respiratory failure within 24 hours. Microbiological and histological examinations raised an invasive pulmonary aspergillosis (IPA). A chronic granulomatous disease was identified as the predisposing factor leading to this severe fungal infection. Chronic granulomatous disease is caused by a reduced ability of phagocytes to mount an oxidative burst due to a defect in the nicotinamide adenine dinucleotide phosphate oxidase. Although IPA occurs usually in severely immunocompromised patients, it should be kept in mind that there are an increasing number of cases developing IPA in the setting of apparent health or to date undiagnosed immunodeficiency that requires further diagnostics.
- Published
- 2012
- Full Text
- View/download PDF
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