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6 results on '"Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology"'

1. Low seroprevalence of COVID-19 in Lao PDR, late 2020

Author

Darouny Phonekeo, Thierry Rose, Sengchanh Kounnavong, Somphavanh Somlor, Nicolas Escriou, Khamsing Vongphayloth, Somphou Sayasone, Mayfong Mayxay, Vilaysone Khounvisith, Phonepadith Xangsayarath, Siriphone Virachith, Antony P. Black, Paul T. Brey, Elodie Calvez, Marc Eloit, Virginie Pommelet, Vincent Lacoste, Judith M. Hübschen, Sarah Temmam, Institut Pasteur du Laos, Réseau International des Instituts Pasteur (RIIP), Lao Tropical Public Health Institute, Institute of Research and Education Development [Vientiane, Laos] (IRED), University of Health Sciences [Vientiane, Laos] (UHS)-Ministry of Health [Laos], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, National Centre for Laboratory and Epidemiology [Vientiane, Laos], Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Département de Santé Globale - Department Global Health, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Institute of Health (LIH), Agence Française de Développement. Additional, Institut Pasteur du Laos, Institute Pasteur, Paris and Luxembourg Ministry of Foreign and European Affairs ('PaReCIDS II')., and TEMMAM, Sarah

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Health Policy, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Public Health, Environmental and Occupational Health, Obstetrics and Gynecology, Age and sex, Article, Psychiatry and Mental health, Infectious Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pediatrics, Perinatology and Child Health, Internal Medicine, Medicine, Seroprevalence, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Christian ministry, Geriatrics and Gerontology, Public aspects of medicine, RA1-1270, business, Demography
Abstract

Background In 2020 Lao PDR had low reported COVID-19 cases but it was unclear whether this masked silent transmission. A seroprevalence study was done August - September 2020 to determine SARS-CoV-2 exposure. Methods Participants were from the general community (n=2433) or healthcare workers (n=666) in five provinces and bat/wildlife contacts (n=74) were from Vientiane province. ELISAs detected anti- SARS-CoV-2 Nucleoprotein (N; n=3173 tested) and Spike (S; n=1417 tested) antibodies. Double-positive samples were checked by IgM/IgG rapid tests. Controls were confirmed COVID-19 cases (n=15) and pre-COVID-19 samples (n=265). Seroprevalence for the general community was weighted to account for complex survey sample design, age and sex. Findings In pre-COVID-19 samples, 5·3%, [95% CI=3·1-8·7%] were anti-N antibody single-positive and 1·1% [0·3-3·5%] were anti-S antibody single positive. None were double positive. Anti-N and anti-S antibodies were detected in 5·2% [4·2-6·5%] and 2·1% [1·1-3·9%] of the general community, 2·0% [1·1-3·3%] and 1·4% [0·5-3·7%] of healthcare workers and 20·3% [12·6-31·0%] and 6·8% [2·8-15·3%] of bat/wildlife contacts. 0·1% [0·02-0·3%] were double positive for anti-N and anti-S antibodies (rapid test negative). Interpretation We find no evidence for significant SARS-CoV-2 circulation in Lao PDR before September 2020. This likely results from early decisive measures taken by the government, social behavior, and low population density. High anti-N /low anti-S seroprevalence in bat/wildlife contacts may indicate exposure to cross-reactive animal coronaviruses with threat of emerging novel viruses. Funding Agence Française de Développement. Additional; Institut Pasteur du Laos, Institute Pasteur, Paris and Luxembourg Ministry of Foreign and European Affairs (“PaReCIDS II”).

Published
2021

2. Cutting Edge: Neutralizing Public Antibody Responses Are an Ancient Form of Defense Conserved in Fish and Mammals

Author

François Huetz, Bertrand Collet, Pierre Bruhns, Rosario Castro, Thierry Rose, J. Oriol Sunyer, Pascal Bochet, Pierre Boudinot, Simon Fillatreau, Sofie Navelsaker, Edwige Quillet, Luc Jouneau, Øystein Evensen, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Faculty of Medicine [Oslo], University of Oslo (UiO), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pennsylvania [Philadelphia], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], The Norwegian University of Life Sciences (NMBU) supported S.N. by an NMBU Ph.D. program, S.N. was also supported by Research Council of Norway (RCN) Project 237315, and Ø.E. received partial funding from RCN Project 239140. J.O.S. was funded by National Institutes of Health Grant 2R01GM085207-09., ANR-16-CE20-0002,Fish-RNAvax,Vaccins ARN éco-compatibles pour l'induction de réponses immunitaires protectrices chez le poisson d'élevage(2016), European Project: 311993,EC:FP7:KBBE,FP7-KBBE-2012-6-singlestage,TARGETFISH(2012), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pennsylvania, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], Immunology, Virus, 03 medical and health sciences, 0302 clinical medicine, Rhabdoviridae Infections, medicine, Immunology and Allergy, Animals, B cell, 030304 developmental biology, Genetics, Mammals, 0303 health sciences, B-Lymphocytes, biology, Host (biology), Repertoire, Vaccination, Fishes, biology.organism_classification, V(D)J Recombination, Clone Cells, Antibody response, medicine.anatomical_structure, Antibody Formation, %22">Fish , Viral hemorrhagic septicemia, Rhabdoviridae, 030215 immunology
Abstract

The repertoire of Abs is generated by genomic rearrangements during B cell differentiation. Although V(D)J rearrangements lead to repertoires mostly different between individuals, recent studies have shown that they contain a substantial fraction of overrepresented and shared “public” clones. We previously reported a strong public IgHμ clonotypic response against the rhabdovirus viral hemorrhagic septicemia virus in a teleost fish. In this study, we identified an IgL chain associated with this public response that allowed us to characterize its functionality. We show that this public Ab response has a potent neutralizing capacity that is typically associated with host protection during rhabdovirus infections. We also demonstrate that the public response is not restricted to a particular trout isogenic line but expressed in multiple genetic backgrounds and may be used as a marker of successful vaccination. Our work reveals that public B cell responses producing generic Abs constitute a mechanism of protection against infection conserved across vertebrates.

Published
2021

3. Adenomatous Polyposis Coli Modulates Actin and Microtubule Cytoskeleton at the Immunological Synapse to Tune CTL Functions

Author

Marie Juzans, Pascal Bochet, Marta Mastrogiovanni, Vincenzo Di Bartolo, Thierry Rose, Céline Cuche, Andrés Alcover, Di Bartolo, Vincenzo, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe labellisée Ligue contre le Cancer, Collège Doctoral, Sorbonne Université (SU), Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from La Ligue Nationale contre le Cancer, Equipe Labellisée 2018, and institutional grants from the Institut Pasteur and INSERM. M.J. was supported by a Ligue Nationale contre le Cancer Doctoral Fellowship and the Institut Pasteur. M.M. is a scholar of the Pasteur Paris University International Doctoral Program, supported by the Institut Pasteur and the European Union Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement 665807 (COFUND-PASTEURDOC). The Unit of Technology and Service Photonic BioImaging core facility is supported by the French National Research Agency France BioImaging (ANR-10–INSB–04, Investments for the Future)., We thank Drs. F. Sepulveda and D. Scott-Algara for scientific advice, J.Y. Tinevez, A. Salles, J. Fernandes and the Unit of Technology and Service Photonic BioImaging facility, Institut Pasteur for technical support and the ICAReB Biological Resources core facility team, Institut Pasteur for providing primary T cell samples. We are grateful to I. Näthke for Abs., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège doctoral [Sorbonne universités], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Immunological Synapses, Adenomatous polyposis coli, Immunology, Adenomatous Polyposis Coli Protein, Mice, Transgenic, Biology, Microtubules, T-Lymphocytes, Regulatory, Immunological synapse, Familial adenomatous polyposis, 03 medical and health sciences, Mice, 0302 clinical medicine, Cell Line, Tumor, Cell polarity, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, Humans, Transcription factor, Cytoskeleton, 030304 developmental biology, Epithelial cell differentiation, 0303 health sciences, NFATC Transcription Factors, NFAT, Cell Differentiation, General Medicine, medicine.disease, Actins, 3. Good health, Cell biology, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Adenomatous Polyposis Coli, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Mutation, biology.protein, Female, 030215 immunology, Signal Transduction
Abstract

Adenomatous polyposis coli (Apc) is a cell polarity regulator and a tumor suppressor associated with familial adenomatous polyposis and colorectal cancer. Apc involvement in T lymphocyte functions and antitumor immunity remains poorly understood. Investigating Apc-depleted human CD8 T cells and CD8 T cells from ApcMin/+ mutant mice, we found that Apc regulates actin and microtubule cytoskeleton remodeling at the immunological synapse, controlling synapse morphology and stability and lytic granule dynamics, including targeting and fusion at the synapse. Ultimately, Apc tunes cytotoxic T cell activity, leading to tumor cell killing. Furthermore, Apc modulates early TCR signaling and nuclear translocation of the NFAT transcription factor with mild consequences on the expression of some differentiation markers. In contrast, no differences in the production of effector cytokines were observed. These results, together with our previous findings on Apc function in regulatory T cells, indicate that Apc mutations may cause a dual damage, first unbalancing epithelial cell differentiation and growth driving epithelial neoplasms and, second, impairing T cell–mediated antitumor immunity at several levels.

Published
2020

4. Cell Biology of T Cell Receptor Expression and Regulation

Author

Balbino Alarcón, Andrés Alcover, Vincenzo Di Bartolo, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)

Subjects
MESH: Signal Transduction, 0301 basic medicine, MESH: CD3 Complex, CD3 Complex, T-Lymphocytes, recycling, MESH: Structure-Activity Relationship, Immunology and Allergy, MESH: Animals, biology, MESH: Receptors, Antigen, T-Cell, MESH: Gene Expression Regulation, Endocytosis, 3. Good health, Cell biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, TCR-CD3, MESH: Endocytosis, Signal transduction, signaling, Signal Transduction, assembly, Endosome, T cell, Immunology, MESH: Immunomodulation, Receptors, Antigen, T-Cell, MESH: Proteolysis, Endosomes, Major histocompatibility complex, Immunomodulation, Structure-Activity Relationship, 03 medical and health sciences, conformational change, Antigen, medicine, Animals, Humans, MESH: Humans, Cell Membrane, T-cell receptor, MESH: Multiprotein Complexes, MESH: T-Lymphocytes, 030104 developmental biology, Gene Expression Regulation, MESH: Endosomes, Multiprotein Complexes, Proteolysis, MESH: Biomarkers, biology.protein, Biomarkers, MESH: Cell Membrane
Abstract

International audience; T cell receptors (TCRs) are protein complexes formed by six different polypeptides. In most T cells, TCRs are composed of αβ subunits displaying immunoglobulin-like variable domains that recognize peptide antigens associated with major histocompatibility complex molecules expressed on the surface of antigen-presenting cells. TCRαβ subunits are associated with the CD3 complex formed by the γ, δ, ε, and ζ subunits, which are invariable and ensure signal transduction. Here, we review how the expression and function of TCR complexes are orchestrated by several fine-tuned cellular processes that encompass (a) synthesis of the subunits and their correct assembly and expression at the plasma membrane as a single functional complex, (b) TCR membrane localization and dynamics at the plasma membrane and in endosomal compartments, (c) TCR signal transduction leading to T cell activation, and (d) TCR degradation. These processes balance each other to ensure efficient T cell responses to a variety of antigenic stimuli while preventing autoimmunity.

Published
2018

5. Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses

Author

Shuai Ding, Thibault Lagache, Jacques Bellalou, Vincenzo Di Bartolo, Salaheddine Mécheri, Neta Regev-Rudzki, François Guillonneau, Sébastien Brûlé, Chris J. Janse, Claudia Demarta-Gatsi, Roger Peronet, Anna Rivkin, Paula Abou Karam, Sidney R. Cohen, Pierre-Henri Commere, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Immunologie Moléculaire, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cytométrie (Plate-forme), Institut Pasteur [Paris], Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Production de Protéines Recombinantes (Plate-Forme) (PRPF), Biophysique Moléculaire (Plate-forme), Analyse d'Images quantitatives (AIQ), Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Weizmann Institute of Science [Rehovot, Israël], Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagopole (CITECH), Institut Pasteur [Paris] (IP), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], MECHERI, Salah, Universiteit Leiden, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Analyse d'images biologiques - Biological Image Analysis (BIA)

Subjects
MAPK/ERK pathway, CD4-Positive T-Lymphocytes, Plasmodium berghei, T cell, T-Lymphocytes, Immunology, Antigen presentation, T cells, Biology, Microbiology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, Extracellular Vesicles, Immune system, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Peptide Elongation Factor 1, Virology, medicine, Biomarkers, Tumor, Animals, Humans, Secretion, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Antigens, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Cell Proliferation, Immune Evasion, 0303 health sciences, Antigen Presentation, immunosuppression, 030306 microbiology, T-cell receptor, Tumor Protein, Translationally-Controlled 1, In vitro, Eukaryotic translation elongation factor 1 alpha 1, 3. Good health, Cell biology, Malaria, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

Protozoan pathogens secrete nanosized particles called extracellular vesicles (EVs) to facilitate their survival and chronic infection. Here, we show the inhibition by Plasmodium berghei NK65 blood stage-derived EVs of the proliferative response of CD4(+) T cells in response to antigen presentation. Importantly, these results were confirmed in vivo by the capacity of EVs to diminish the ovalbumin-specific delayed type hypersensitivity response. We identified two proteins associated with EVs, the histamine releasing factor (HRF) and the elongation factor 1 alpha (EF-1 alpha) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF- and EF-1 alpha-deficient parasites failed to inhibit T cell responses in vitro and in vivo. At the level of T cells, we demonstrated that EVs from WT parasites dephosphorylate key molecules (PLC gamma 1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF-1 alpha alone or in combination with HRF conferred a long-lasting antiparasite protection and immune memory. In conclusion, we identified a new mechanism by which P. berghei-derived EVs exert their immunosuppressive functions by altering T cell responses. The identification of two highly conserved immune suppressive factors offers new conceptual strategies to overcome EV-mediated immune suppression in malaria-infected individuals.

Published
2019

6. Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function

Author

Navas, Victor H, Cuche, Céline, Alcover, Andres, Di Bartolo, Vincenzo, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was funded by grants from the Institut Pasteur, the French National Center for Scientific Research (CNRS), French National Institute of Health and Medical Research (Inserm), the Ligue Contre le Cancer–Comité de Paris (grants nr. RS12/75-107 and RS13/75-30 to V.D.B.) and the Agence National de la Recherche (grant nr. ANR-11-BSV3-0025 to A.A)., We thank Drs. J. Bouchet and S Aguera (Lymphocyte Cell Biology Unit, Institut Pasteur) for critical reading the manuscript, Drs. P. Bruhns, F. Jönsson and C. Gillis (Antibodies in Therapy and Pathology Unit, Institut Pasteur) for helpful discussions, reagents and advice for some experiments, G. Millot and T. Obadia (Bioinformatics and Biostatistics Hub–C3BI, Institut Pasteur, USR 3756, CNRS) for their help with statistical analysis. We also thank the CIPHE-Phenomin (Inserm, US012) team for generating the SLP76-S376A knock-in mouse line and, in particular, Lillia Hadjem for the high-content flow cytometry immunophenotyping. Finally, we thank the Flow Cytometry facility of the Institut Pasteur for help in T cell sorting. V.H.N. was funded by a doctoral contract of the French Ministry of Higher Education and Research, ANR-11-BSV3-0025,LEUKOSITRACY,Coordination de la signalisation cellulaire, du cytosquelette et du trafic intracellaire pour le contrôle de fonctions leukocytaires majeures(2011), Di Bartolo, Vincenzo, BLANC - Coordination de la signalisation cellulaire, du cytosquelette et du trafic intracellaire pour le contrôle de fonctions leukocytaires majeures - - LEUKOSITRACY2011 - ANR-11-BSV3-0025 - BLANC - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
Physiology, T-Lymphocytes, lcsh:Medicine, Biochemistry, Mice, White Blood Cells, Spectrum Analysis Techniques, Animal Cells, Immune Physiology, Serine, Medicine and Health Sciences, Phosphorylation, Post-Translational Modification, lcsh:Science, Staining, Innate Immune System, Thymocytes, T Cells, Stem Cells, Cell Staining, Flow Cytometry, Precipitation Techniques, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Spectrophotometry, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Cytokines, Cytophotometry, Cellular Types, Anatomy, Signal Transduction, Research Article, Hematopoietic Progenitor Cells, Immune Cells, Immunology, Mice, Transgenic, Research and Analysis Methods, Lymphatic System, Animals, Humans, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Blood Cells, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, Molecular Development, Phosphoproteins, Mice, Inbred C57BL, Specimen Preparation and Treatment, Immune System, lcsh:Q, Lymph Nodes, Developmental Biology
Abstract

International audience; The adapter protein SLP76 is a key orchestrator of T cell receptor (TCR) signal transduction. We previously identified a negative feedback loop that modulates T cell activation, involving phosphorylation of Ser376 of SLP76 by the hematopoietic progenitor kinase 1 (HPK1). However, the physiological relevance of this regulatory mechanism was still unknown. To address this question, we generated a SLP76-S376A-expressing knock-in mouse strain and investigated the effects of Ser376 mutation on T cell development and function. We report here that SLP76-S376A-expressing mice exhibit normal thymocyte development and no detectable phenotypic alterations in mature T cell subsets or other lymphoid and myeloid cell lineages. Biochemical analyses revealed that mutant T cells were hypersensitive to TCR stimulation. Indeed, phosphorylation of several signaling proteins, including SLP76 itself, phospholipase Cγ1 and the protein kinases AKT and ERK1/2, was increased. These modifications correlated with increased Th1-type and decreased Th2-type cytokine production by SLP76-S376A T cells, but did not result in significant changes of proliferative capacity nor activation-induced cell death susceptibility. Hence, our results reveal that SLP76-Ser376 phosphorylation does not mediate all HPK1-dependent regulatory effects in T cells but it fine-tunes helper T cell responses.

Published
2016

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