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1. Low Levels of Natural Anti-α-N-Acetylgalactosamine (Tn) Antibodies Are Associated With COVID-19

Author

Adrien Breiman, Nathalie Ruvoën-Clouet, Marie Deleers, Tiffany Beauvais, Nicolas Jouand, Jézabel Rocher, Nicolai Bovin, Nathalie Labarrière, Hanane El Kenz, Jacques Le Pendu, Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Université libre de Bruxelles (ULB), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), the Russian Academy of Sciences [Moscow, Russia] (RAS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Russian Academy of Sciences [Moscow] (RAS), Dupuis, Christine, and Bernardo, Elizabeth

Subjects
Microbiology (medical), Microbiologie et protistologie [parasitologie hum. et anim.], Glycan, [SDV]Life Sciences [q-bio], Tn antigen, lcsh:QR1-502, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030204 cardiovascular system & hematology, Microbiology, Asymptomatic, Epitope, lcsh:Microbiology, N-Acetylgalactosamine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, natural antibodies, Antibody Repertoire, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, O-glycans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, COVID-19, [SDV] Life Sciences [q-bio], Microbiologie et protistologie [entomologie,phytoparasitolog.], chemistry, Immunology, biology.protein, Antibody, medicine.symptom, Microbiologie et protistologie [bacteriol.virolog.mycolog.], histo-blood group antigens
Abstract

Human serum contains large amounts of anti-carbohydrate antibodies, some of which may recognize epitopes on viral glycans. Here, we tested the hypothesis that such antibodies may confer protection against COVID-19 so that patients would be preferentially found among people with low amounts of specific anti-carbohydrate antibodies since individual repertoires vary considerably. After selecting glycan epitopes commonly represented in the human anti-carbohydrate antibody repertoire that may also be expressed on viral glycans, plasma levels of the corresponding antibodies were determined by ELISA in 88 SARS-CoV-2 infected individuals, including 13 asymptomatic, and in 82 non-infected controls. We observed that anti-Tn antibodies levels were significantly lower in patients as compared to non-infected individuals. This was not observed for any of the other tested carbohydrate epitopes, including anti-αGal antibodies used as a negative control since the epitope cannot be synthesized by humans. Owing to structural homologies with blood groups A and B antigens, we also observed that anti-Tn and anti-αGal antibodies levels were lower in blood group A and B, respectively. Analyses of correlations between anti-Tn and the other anti-carbohydrates tested revealed divergent patterns of correlations between patients and controls, suggesting qualitative differences in addition to the quantitative difference. Furthermore, anti-Tn levels correlated with anti-S protein levels in the patients’ group, suggesting that anti-Tn might contribute to the development of the specific antiviral response. Overall, this first analysis allows to hypothesize that natural anti-Tn antibodies might be protective against COVID-19., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021
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2. PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy

Author

Valentin Voillet, Tiffany Beauvais, Brigitte Dréno, Charles Nardin, Régis Josien, Camille Dabrowski, Nathalie Labarrière, Stanley R. Riddell, Sylvain Simon, Candice D. Church, Nicolas Jouand, Raphael Gottardo, Olivier Adotevi, Amir Khammari, François Aubin, Steven P. Fling, Cécile Braudeau, Martin A. Cheever, Virginie Vignard, Paul Nghiem, Samuel Rulli, Nirasha Ramchurren, Caroline Laheurte, Zhong Wu, Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Centre hospitalier universitaire de Nantes (CHU Nantes), Qiagen Sciences [Frederick, MD, USA], Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de dermatologie (CHRU Besançon), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), SIRIC ILIAD (INCA-DGOS-Inserm_12558)BMS FoundationLigue contre le CancerRégion Pays de la Loire, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Département de dermatologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques-Université de Franche-Comté (UFC), LABARRIERE, Nathalie, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, 0302 clinical medicine, T-Lymphocyte Subsets, Immunotherapy Biomarkers, Immunology and Allergy, Cytotoxic T cell, Receptors, Immunologic, Immune Checkpoint Inhibitors, RC254-282, education.field_of_study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, medicine.anatomical_structure, Oncology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Molecular Medicine, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Receptors, CXCR5, costimulatory and inhibitory T-Cell receptors, T cell, Immunology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, TIGIT, Predictive Value of Tests, medicine, melanoma, Humans, education, Pharmacology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Gene signature, Carcinoma, Merkel Cell, 030104 developmental biology, Cancer research, CD8
Abstract

BackgroundClinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.MethodsWe isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.ResultsWe documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.ConclusionsOur results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.

Published
2020
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3. Immunotherapy With Antiprogrammed Cell Death 1 Antibody Improves Outcome in a Mouse Model of Spinal Cord Injury Followed by Staphylococcus aureus Pneumonia

Author

Antoine Roquilly, Karim Asehnoune, Xavier Ambrosi, Alexis Broquet, Juliette Desfrançois, Cédric Jacqueline, Tiphaine Ruggeri, Frédéric Altare, ALTARE, Frédéric, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)

Subjects
Staphylococcus aureus, Programmed cell death, Pathology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, T-Lymphocytes, medicine.medical_treatment, Critical Care and Intensive Care Medicine, medicine.disease_cause, Antibodies, programmed cell death 1 receptor, 03 medical and health sciences, 0302 clinical medicine, Pneumonia, Bacterial, Animals, Medicine, Spinal cord injury, Spinal Cord Injuries, Depression (differential diagnoses), Mice, Inbred BALB C, immunosuppression, biology, business.industry, Histocompatibility Antigens Class II, 030208 emergency & critical care medicine, Dendritic Cells, Immunotherapy, brain injury, medicine.disease, Spinal cord, spinal cord injury, 3. Good health, Disease Models, Animal, Pneumonia, medicine.anatomical_structure, 030228 respiratory system, biology.protein, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Disease Susceptibility, immunotherapy, Antibody, business, Spleen
Abstract

International audience; Objectives: In patients with spinal cord injury, spinal cord injury-immune depression syndrome induces pneumonia. We aimed to develop a new spinal cord injury-immune depression syndrome mouse model and to test antiprogrammed cell death 1 therapy. Design: Experimental study. Setting: Research laboratory. Subjects: RjOrl: SWISS and BALB/cJ mice. Interventions: Mouse model of spinal cord injury-immune depression syndrome followed by a methicillin-susceptible Staphylococcus aureus pneumonia. Lung injuries were assessed by histologic analysis. Membrane markers and intracytoplasmic cytokines were assessed by flow cytometry. Cytokine production was assessed by quantitative polymerase chain reaction (messenger RNA) and enzyme-linked immunosorbent assay (protein). Animals were treated with blocking antiprogrammed cell death 1 antibodies (intraperitoneal injection). Measurements and Main Results: Spinal cord injury mice were more susceptible to methicillin-susceptible S. aureus pneumonia (increased mortality rate). An early inflammatory response was observed in spinal cord injury mice characterized in lungs by a decreased percentage of aerated tissue, an increased production of proinflammatory cytokines (tumor necrosis factor-α). In spleen, an increased expression of major histocompatibility complex class II molecules on dendritic cells, and an increased production of pro-inflammatory cytokines (interleukin-12, interferon-γ) was observed. Following this pulmonary and systemic inflammation, spinal cord injury-immune depression syndrome was observed in spleens as acknowledged by a decrease of spleen's weight, a lymphopenia, a decrease of major histocompatibility complex class II expression on dendritic cells. An increase of interleukin-10 production and the increase of a cell exhaustion marker expression, programmed cell death 1 receptor on T-cell were also observed. Blockade of programmed cell death 1 molecules, improved survival of spinal cord injury infected mice and enhanced interferon-γ production by natural killer T cells as well as number of viable CD4 + T cells. Conclusions: This model of spinal cord injury in mice mimics a clinical scenario rendering animals prone to a secondary pneumonia. We show for the first time an acute T-cell exhaustion-like phenomenon following an initial inflammatory response. Finally, inhibition of exhaustion pathway should be considered as a new therapeutic option to overcome spinal cord injury-immune depression syndrome and to decrease the rate of nosocomial pneumonia. (Crit Care Med 2019; 47:e28-e35) Key Words: brain injury; immunosuppression; immunotherapy; programmed cell death 1 receptor; spinal cord injury N osocomial infections are independent risk factors for poor neurologic outcome after motor complete spinal cord injury (SCI) (1). SCI induces a severe initial systemic inflammatory response followed by an intense period of immunosuppression which is recognized as an independent risk factor for infection (1, 2). Studies in human and rodent SCI models have already investigated the specific

Published
2019
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4. Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis

Author

Mickael Vourc'h, Marion Davieau, Jose A Villadangos, Antoine Roquilly, Hamish E G McWilliam, Vanessa Gauttier, Abderrahmane Sadek, Raphaël Cinotti, Alexis Broquet, Cédric Jacqueline, Cynthia Fourgeux, Alice Molle, Frédéric Altare, Nadege Marec, Karim Asehnoune, Jeremie Poschmann, Paul Rooze, Barbara Misme-Aucouturier, Tanguy Chaumette, Le Bihan, Sylvie, Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Anesthésie Réanimation chirurgicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], University of Melbourne, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Moulay Ismail (UMI), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Dendritic cells and immunoregulation in transplantation and immunopathology (Team 1 - U1064 Inserm - CRTI), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
0301 basic medicine, Phagocytosis, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Systemic inflammation, Immune tolerance, Sepsis, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Lung, biology, business.industry, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Pneumonia, 030104 developmental biology, medicine.anatomical_structure, biology.protein, medicine.symptom, Antibody, business, 030215 immunology
Abstract

International audience; Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.

Published
2020
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5. IL-9 promotes the survival and function of human melanoma-infiltrating CD4+CD8+double-positive T cells

Author

Nathalie Labarrière, Yves Delneste, Nadine Gervois, Romain Oger, Houssem Benlalam, Diane Raingeard de la Blétière, Tiphaine Parrot, Amir Khammari, Laurence Preisser, Mathilde Allard, Anne Coutolleau, Juliette Desfrançois, Philippe Guardiola, Brigitte Dréno, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Plateforme SNP, Transcriptome & Epigénomique, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), GMP Unit of Cellular Therapy, Centre hospitalier universitaire de Nantes (CHU Nantes), Unit of Skin Cancer, Canceropole Grand Ouest, Région Pays de la Loire, ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, and Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID

Subjects
CD4-Positive T-Lymphocytes, Cytotoxicity, Immunologic, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, Immunology, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, CD8-Positive T-Lymphocytes, Biology, Lymphocyte Activation, 03 medical and health sciences, Interleukin 21, Lymphocytes, Tumor-Infiltrating, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, T-Lymphocyte Subsets, Humans, Immunology and Allergy, Cytotoxic T cell, Interleukin 9, Melanoma, Cells, Cultured, Receptors, Interleukin-9, Interleukin-9, Degranulation, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, T lymphocyte, 3. Good health, Granzyme B, 030104 developmental biology, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, CD8
Abstract

International audience; We previously demonstrated an accumulation of tumor-reactive CD4 + CD8 + double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8 + counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R high DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses. Keywords: CD4 + CD8 + double-positive T lymphocyte r IL-9R r IL-9 r Melanoma r TIL Additional supporting information may be found in the online version of this article at the publisher's web-site

Published
2016
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6. Expression of CCR6 and CXCR6 by Gut-Derived CD4+/CD8α+ T-Regulatory Cells, Which Are Decreased in Blood Samples From Patients With Inflammatory Bowel Diseases

Author

Chantal Bridonneau, Emmanuel Montassier, Amandine Le Roy, Francine Jotereau, Céline Bossard, Arnaud Bourreille, Justine Mathé, Nadege Marec, Harry Sokol, Guillaume Sarrabayrouse, Frédéric Altare, Emmanuelle Godefroy, Anne Jarry, Joudy Alameddine, Juliette Desfrançois-Noël, Elise Kerdreux, Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des Urgences [CHU Nantes], Hôtel-Dieu de Nantes, Microbiotes, Hôtes, Antibiotiques et Résistances bactériennes (MiHAR) (MiHAR), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Commensal and probiotics-host interactions laboratory [INRA, Jouy-en-Josas], Institut National de la Recherche Agronomique (INRA), Vall d’Hebron Research Institute (VHIR), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by ANR (Microbiota-induced Treg) and ARMINA (2012 09680)., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Interactions des Bactéries Commensales et Probiotiques avec l'Hôte (Probihôte), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech-Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, Host-pathogen interactions in the regulation of immune responses (CRCINA - Département INCIT - Equipe 5), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Plate-forme CytoCell [Nantes] (CRCINA – Unité Inserm U1232), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Vall d’Hebron Institute of Research [Barcelona, Spain], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Gastroentérologie [AP-HP Hôpital Saint-Antoine], and AP-HP - Hôpital Saint-Antoine

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Population, Faecalibacterium prausnitzii, C-C chemokine receptor type 6, Inflammatory bowel disease, Immune Regulation, 03 medical and health sciences, Intestinal mucosa, medicine, Antigen-presenting cell, education, education.field_of_study, Hepatology, biology, Bacteria, business.industry, Microbiota, Gastroenterology, Interleukin, medicine.disease, biology.organism_classification, 3. Good health, Interleukin 10, 030104 developmental biology, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, T-Cell Response
Abstract

International audience; BACKGROUND & AIMS:Faecalibacterium prausnitzii, a member of the Clostridium IV group of the Firmicutes phylum that is abundant in the intestinal microbiota, has anti-inflammatory effects. The relative level of F prausnitzii is decreased in fecal samples from patients with inflammatory bowel diseases (IBDs) compared with healthy individuals. Reduced F prausnitzii was correlated with relapse of Crohn's disease after surgery. We identified, in human colonic mucosa and blood, a population of T regulatory type 1-like T regulatory (TREG) cells that express CD4 and CD8α (DP8α T cells) and are specific for F prausnitzii. We aimed to determine whether they are altered in patients with IBD.METHODS:We isolated DP8α T cells from human colon lamina propria and blood samples and used flow cytometry to detect markers of cells that are of colon origin. We quantified DP8α cells that express colon-specific markers in blood samples from 106 patients with IBD, 12 patients with infectious colitis, and 35 healthy donors (controls). We identified cells that respond to F prausnitzii. Cells were stimulated with anti-CD3, and their production of interleukin 10 was measured by enzyme-linked immunosorbent assay. We compared the frequency and reactivity of cells from patients vs controls using the 2-sided Student t test or 1-way analysis of variance.RESULTS:Circulating DP8α T cells that proliferate in response to F prausnitzii express the C-C motif chemokine receptor 6 (CCR6) and C-X-C motif chemokine receptor 6 (CXCR6). These cells also have features of TREG cells, including production of IL-10 and inhibition of T-cell proliferation via CD39 activity. The proportion of circulating CCR6+/CXCR6+ DP8α T cells was significantly reduced (P < .0001) within the total population of CD3+ T cells from patients with IBD compared with patients with infectious colitis or controls. A threshold of

Published
2018
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