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1. A Virus Hosted in Malaria-Infected Blood Protects against T Cell-Mediated Inflammatory Diseases by Impairing DC Function in a Type I IFN-Dependent Manner

Author

Ali Hassan, Myriam F. Wlodarczyk, Mehdi Benamar, Emilie Bassot, Anna Salvioni, Sahar Kassem, Antoine Berry, Abdelhadi Saoudi, and Nicolas Blanchard

Subjects
CD4 T cell, RNA virus, autoimmunity, coinfection, dendritic cells, inflammation, Microbiology, QR1-502
Abstract

ABSTRACT Coinfections shape immunity and influence the development of inflammatory diseases, resulting in detrimental or beneficial outcome. Coinfections with concurrent Plasmodium species can alter malaria clinical evolution, and malaria infection itself can modulate autoimmune reactions. Yet, the underlying mechanisms remain ill defined. Here, we demonstrate that the protective effects of some rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus cohosted in malaria-parasitized blood. We show that live and extracts of blood parasitized by Plasmodium berghei K173 or Plasmodium yoelii 17X YM, protect against P. berghei ANKA-induced experimental cerebral malaria (ECM) and myelin oligodendrocyte glycoprotein (MOG)/complete Freund’s adjuvant (CFA)-induced experimental autoimmune encephalomyelitis (EAE), and that protection is associated with a strong type I interferon (IFN-I) signature. We detected the presence of the RNA virus lactate dehydrogenase-elevating virus (LDV) in the protective Plasmodium stabilates and we established that LDV infection alone was necessary and sufficient to recapitulate the protective effects on ECM and EAE. In ECM, protection resulted from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and impairment of their ability to produce interleukin (IL)-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, LDV infection induced IFN-I-mediated abrogation of IL-23, thereby preventing the differentiation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing encephalitogenic CD4+ T cells. Our work identifies a virus cohosted in several Plasmodium stabilates across the community and deciphers its major consequences on the host immune system. More generally, our data emphasize the importance of considering contemporaneous infections for the understanding of malaria-associated and autoimmune diseases. IMPORTANCE Any infection modifies the host immune status, potentially ameliorating or aggravating the pathophysiology of a simultaneous inflammatory condition. In the course of investigating how malaria infection modulates the severity of contemporaneous inflammatory diseases, we identified a nonpathogenic mouse virus in stabilates of two widely used rodent parasite lines: Plasmodium berghei K173 and Plasmodium yoelii 17X YM. We established that the protective effects of these Plasmodium lines on cerebral malaria and multiple sclerosis are exclusively due to this virus. The virus induces a massive type I interferon (IFN-I) response and causes quantitative and qualitative defects in the ability of dendritic cells to promote pathogenic T cell responses. Beyond revealing a possible confounding factor in rodent malaria models, our work uncovers some bases by which a seemingly innocuous viral (co)infection profoundly changes the immunopathophysiology of inflammatory diseases.

Published
2020
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2. A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire

Author

Isabelle Bernard, Antoine Sacquin, Sahar Kassem, Mehdi Benamar, Céline Colacios, Mylène Gador, Corine Pérals, Nicolas Fazilleau, and Abdelhadi Saoudi

Subjects
myasthenia gravis, T cells, Vav1, animal models, T cell repertoire, Immunologic diseases. Allergy, RC581-607
Abstract

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell receptor (TCR) signals and plays an important role in T cell development and activation. Previous genetic studies identified a natural variant of Vav1 characterized by the substitution of an arginine (R) residue by a tryptophane (W) at position 63 (Vav1R63W). This variant impacts Vav1 adaptor functions and controls susceptibility to T cell-mediated neuroinflammation. To assess the implication of this Vav1 variant on the susceptibility to antibody-mediated diseases, we used the animal model of myasthenia gravis, experimental autoimmune myasthenia gravis (EAMG). To this end, we generated a knock-in (KI) mouse model bearing a R to W substitution in the Vav1 gene (Vav1R63W) and immunized it with either torpedo acetylcholine receptor (tAChR) or the α146-162 immunodominant peptide. We observed that the Vav1R63W conferred increased susceptibility to EAMG, revealed by a higher AChR loss together with an increased production of effector cytokines (IFN-γ, IL-17A, GM-CSF) by antigen-specific CD4+ T cells, as well as an increased frequency of antigen-specific CD4+ T cells. This correlated with the emergence of a dominant antigen-specific T cell clone in KI mice that was not present in wild-type mice, suggesting an impact on thymic selection and/or a different clonal selection threshold following antigen encounter. Our results highlight the key role of Vav1 in the pathophysiology of EAMG and this was associated with an impact on the TCR repertoire of AChR reactive T lymphocytes.

Published
2018
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3. Oral Administration of the Probiotic Strain Escherichia coli Nissle 1917 Reduces Susceptibility to Neuroinflammation and Repairs Experimental Autoimmune Encephalomyelitis-Induced Intestinal Barrier Dysfunction

Author

Thomas Secher, Sahar Kassem, Mehdi Benamar, Isabelle Bernard, Michele Boury, Frederick Barreau, Eric Oswald, and Abdelhadi Saoudi

Subjects
Escherichia coli Nissle 1917, experimental autoimmune encephalomyelitis, probiotic, intestinal permeability, encephalitogenic T-cell, central nervous system, Immunologic diseases. Allergy, RC581-607
Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with an increasing incidence in developed countries. Recent reports suggest that modulation of the gut microbiota might be one promising therapy for MS. Here, we investigated whether the probiotic Escherichia coli strain Nissle 1917 (ECN) could modulate the outcome of experimental autoimmune encephalomyelitis (EAE), a murine model of MS. We evidenced that daily oral treatment with ECN, but not with the archetypal K12 E. coli strain MG1655, reduced the severity of EAE induced by immunization with the MOG35–55 peptide. This beneficial effect was associated with a decreased secretion of inflammatory cytokines and an increased production of the anti-inflammatory cytokine IL-10 by autoreactive CD4 T cells, both in peripheral lymph nodes and CNS. Interestingly, ECN-treated mice exhibited increased numbers of MOG-specific CD4+ T cells in the periphery contrasting with severely reduced numbers in the CNS, suggesting that ECN might affect T cell migration from the periphery to the CNS through a modulation of their activation and/or differentiation. In addition, we demonstrated that EAE is associated with a profound defect in the intestinal barrier function and that treatment with ECN, but not with MG1655, repaired intestinal permeability dysfunction. Collectively, our data reveal that EAE induces a disruption of the intestinal homeostasis and that ECN protects from disease and restores the intestinal barrier function.

Published
2017
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4. A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.

Author

Sahar Kassem, Guillaume Gaud, Isabelle Bernard, Mehdi Benamar, Anne S Dejean, Roland Liblau, Gilbert J Fournié, Céline Colacios, Bernard Malissen, and Abdelhadi Saoudi

Subjects
Genetics, QH426-470
Abstract

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation.

Published
2016
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5. Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Author

Cédric Auffray, Guilhem Lalle, Charlotte Pouchy, Yenkel Grinberg-Bleyer, David Sleurs, Harald Wajant, Gilles Marodon, Sylvie Grégoire, Yannis Lombardi, Bruno Lucas, Maryam Khosravi, Emilie Ronin, Gaëlle H. Martin, Noémie Chanson, Sahar Kassem, Benoît L. Salomon, Morgane Hilaire, Armanda Casrouge, Gestionnaire, Hal Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Centre Léon Bérard [Lyon], University Hospital of Würzburg, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Central Nervous System, 0301 basic medicine, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, T cell, [SDV]Life Sciences [q-bio], TNF, Priming (immunology), Inflammation, chemical and pharmacologic phenomena, medicine.disease_cause, T-Lymphocytes, Regulatory, Autoimmunity, Mice, 03 medical and health sciences, 0302 clinical medicine, Bone Marrow, medicine, Animals, Humans, Receptors, Tumor Necrosis Factor, Type II, CTLA-4 Antigen, autoimmune diseases, Mice, Knockout, Autoimmune disease, Multidisciplinary, business.industry, Experimental autoimmune encephalomyelitis, FOXP3, hemic and immune systems, Biological Sciences, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Tumor necrosis factor alpha, Positive Regulatory Domain I-Binding Factor 1, medicine.symptom, business, Treg cells, Signal Transduction
Abstract

International audience; CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.

Published
2021

6. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Author

Stanislas Goriely, Marie-Véronique Joubert, Tobias Bald, Mark J. Smyth, Ludovic Martinet, Elena Morandi, Loïc Dupré, Laure Buisson, Nadège Carrié, Marianne Weulersse, Guillaume Gaud, Marie Le Moine, Thomas Gossye, Anne Dejean, Hervé Avet-Loiseau, Ashmitha Sundarrajan, Assia Asrir, Andrea C. Pichler, Michaël Pérès, Abdelhadi Saoudi, Alejandra Martinez, Julien Mazieres, Sahar Kassem, Elisa Brauns, Els Verhoeyen, Indrajit Das, Sabrina Maheo, Matthias Braun, Vera Pancaldi, Clara Maria Scarlata, Marine Cuisinier, Maha Ayyoub, Laura Do Souto, Lea Lemaitre, Arantxa Agesta, Camille Guillerey, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université libre de Bruxelles (ULB), Centre de Physiopathologie Toulouse Purpan (CPTP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP)

Subjects
0301 basic medicine, MESH: Neoplasms / immunology, 8 Supplementary Figures, Lymphocyte, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH: Programmed Cell Death 1 Receptor / immunology, CD226 (DNAM-1), MESH: Receptors, Antigen, T-Cell / immunology, MESH: Neoplasms / therapy, TCR signaling, 0302 clinical medicine, Cancer immunotherapy, MESH: Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, ComputingMilieux_MISCELLANEOUS, T cell exhaustion, MESH: Signal Transduction / immunology, MESH: CD8-Positive T-Lymphocytes / immunology, 3. Good health, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Immunotherapy, MESH: Transcriptome / immunology, Immunology, Eomesodermin, 8 Figures, Biology, MESH: Antigens, Differentiation, T-Lymphocyte / immunology, Co-stimulation, 03 medical and health sciences, tumor immune escape, MESH: Mice, Inbred C57BL, MESH: Immune Checkpoint Inhibitors / immunology, medicine, MESH: Tumor Microenvironment / immunology, MESH: Mice, 96 References CD8 + T lymphocytes, Tumor microenvironment, MESH: Humans, immune checkpoint blockade, MESH: T-Box Domain Proteins / immunology, Immune checkpoint, MESH: Immunotherapy / methods, Sciences biomédicales, 030104 developmental biology, Cancer research, CD8
Abstract

Through complementary approaches, involving cancer patients’ samples and relevant mouse tumor models, Weulersse et al. reveal that CD8 T cells in the tumor microenvironment lose expression of the activating receptor CD226 (DNAM-1) in a manner that is Eomes dependent. CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226 CD8 T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8 tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226 mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8 T cell function and limits the efficacy of cancer immunotherapy.

Published
2020

7. The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4 + T cells

Author

Julien Familiades, Guillaume Gaud, Abdelhadi Saoudi, Bernard Monsarrat, Romain Roncagalli, Karima Chaoui, Anne Gonzalez de Peredo, Bernard Malissen, Odile Burlet-Schiltz, Sahar Kassem, Isabelle Bernard, Céline Colacios, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, VAV1, CD226, T cell, [SDV]Life Sciences [q-bio], medicine.disease_cause, Biochemistry, Autoimmunity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, medicine, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Chemistry, T-cell receptor, Tyrosine phosphorylation, Cell Biology, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 17, 030215 immunology
Abstract

The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4(+) T cells. Moreover, co-engagement of the TCR and a risk variant of CD226 that is associated with autoimmunity (rs763361) further enhanced VAV1 activation and IL-17 production. Thus, our study reveals that a VAV1-based, synergistic cross-talk exists between the TCR and CD226 during both physiological and pathological T cell responses and provides a rational basis for targeting CD226 for the management of autoimmune diseases.

Published
2018

8. Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment

Author

Hervé Avet-Loiseau, Eva Maria Putz, Marie Lorraine Chretien, Kyohei Nakamura, Ludovic Martinet, Seth L. Masters, Marta Chesi, Tobias Bald, Irmgard Förster, Alice Cleynen, Mark J. Smyth, Camille Guillerey, Sahar Kassem, Geoffrey R. Hill, Slavica Vuckovic, P. Leif Bergsagel, Institut Montpelliérain Alexander Grothendieck (IMAG), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Montpellier ( UM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps [Toulouse], Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
0301 basic medicine, Male, Cancer Research, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Immune tolerance, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, Immune Tolerance, Tumor Microenvironment, Medicine, Animals, Humans, Multiple myeloma, ComputingMilieux_MISCELLANEOUS, Tumor microenvironment, business.industry, Myeloid-Derived Suppressor Cells, Interleukin-18, Interleukin, Cell Biology, Immunotherapy, medicine.disease, Prognosis, Survival Analysis, 3. Good health, Up-Regulation, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Oncology, Myeloid-derived Suppressor Cell, Cancer research, Disease Progression, Female, Bone marrow, business, Multiple Myeloma, Neoplasm Transplantation
Abstract

Tumor-promoting inflammation and avoiding immune destruction are hallmarks of cancer. Here, we demonstrate that the pro-inflammatory cytokine interleukin (IL)-18 is critically involved in these hallmarks in multiple myeloma (MM). Mice deficient for IL-18 were remarkably protected from Vk∗MYC MM progression in a CD8+ T cell-dependent manner. The MM-niche-derived IL-18 drove generation of myeloid-derived suppressor cells (MDSCs), leading to accelerated disease progression. A global transcriptome analysis of the immune microenvironment in 73 MM patients strongly supported the negative impact of IL-18-driven MDSCs on T cell responses. Strikingly, high levels of bone marrow plasma IL-18 were associated with poor overall survival in MM patients. Furthermore, our preclinical studies suggested that IL-18 could be a potential therapeutic target in MM.

Published
2018

9. A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation

Author

Isabelle Bernard, Céline Colacios, Abdelhadi Saoudi, Bernard Malissen, Anne Dejean, Mehdi Benamar, Sahar Kassem, Roland S. Liblau, Gilbert J. Fournié, Guillaume Gaud, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-08-GENO-0041,VAV1GENOPAT,VAV1: un noeud de signalisation contrôlant l'homéostasie du système immunitaire et les maladies immunes(2008), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Central Nervous System, Male, 0301 basic medicine, Cell signaling, Cancer Research, Physiology, Signal transduction, Mouse models, T-Lymphocytes, Regulatory, White Blood Cells, Mice, Interleukin 21, 0302 clinical medicine, Animal Cells, Immune Physiology, Medicine and Health Sciences, Cytotoxic T cell, IL-2 receptor, Genetics (clinical), Staining, Innate Immune System, Thymocytes, TCR signaling cascade, Stem Cells, ZAP70, Signaling cascades, CD28, Forkhead Transcription Factors, Animal Models, Regulatory T cells, Natural killer T cell, Cell staining, 3. Good health, Phenotype, medicine.anatomical_structure, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, Cellular Types, Research Article, Encephalomyelitis, Autoimmune, Experimental, Hematopoietic Progenitor Cells, lcsh:QH426-470, Immune Cells, T cell, Immunology, Receptors, Antigen, T-Cell, T cells, Thymus Gland, Biology, Research and Analysis Methods, 03 medical and health sciences, T helper cells, Model Organisms, Genetics, medicine, Animals, Genetic Predisposition to Disease, Proto-Oncogene Proteins c-vav, Antigen-presenting cell, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Inflammation, Blood Cells, Polymorphism, Genetic, Biology and Life Sciences, Genetic Variation, Cell Biology, Molecular Development, Molecular biology, Rats, Mice, Inbred C57BL, lcsh:Genetics, 030104 developmental biology, Specimen Preparation and Treatment, Immune System, Calcium, Developmental Biology, 030215 immunology
Abstract

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation., Author Summary The understanding of the physiological role of Vav1, a key regulator of T cell receptor signaling, was primarily inferred from studies using Vav1-deficient mice. Such models, however, provide little insight on how polymorphisms leading to quantitative changes in Vav1 activity could affect immune system functions. In the present study, we focused on a recently identified Vav1R63W natural variant that has been supposed to play a central role in the susceptibility to neuroinflammation. Using a Vav1R63W knock-in mouse model, we show that Vav1R63W leads to defects in adaptor functions and reduces the susceptibility to experimental autoimmune encephalomyelitis, together with an intrinsic defect in the production of Th1/Th17 cytokines by autoreactive effector CD4 T cells. Thus, our study highlights the importance of Vav1 adaptor functions in CD4 T cells differentiation and suggests that genetic or acquired alterations of this Vav1 function could play a major role in susceptibility to Th1/Th17 mediated diseases.

Published
2016

10. An epistatic interaction between Themis1 and Vav1 modulates regulatory T cell function and inflammatory bowel disease development

Author

Dominique Lagrange, Abdelhadi Saoudi, Gilbert J. Fournié, Anne Dejean, Renaud Lesourne, Isabelle Bernard, Olivier Andreoletti, Sahar Kassem, Marianne Chabod, Christophe Pedros, Guillaume Gaud, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-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), Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, INSERM, Association Francaise contre les Myopathies, Agence Nationale de la Recherche [ANR-08-GENO-041-01], Fondation pour la Recherche Medicale [DEQ2000326531], Association de Recherche sur la Sclerose en Plaques, Region Midi-Pyrenees, Ministere de l'Education Nationale de la Recherche et de la Technologie, Fondation pour la Recherche Medicale, Centre National de la Recherche Scientifique, European Project: 242210,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,FIGHT-MG(2009), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), ProdInra, Migration, and Myasthenias, a group of immune mediated neurological diseases: from etiology to therapy. - FIGHT-MG - - EC:FP7:HEALTH2009-12-01 - 2014-05-31 - 242210 - VALID

Subjects
MAPK/ERK pathway, Male, VAV1, Regulatory T cell, [SDV]Life Sciences [q-bio], Immunology, Congenic, Receptors, Antigen, T-Cell, Biology, T-Lymphocytes, Regulatory, Intestinal mucosa, T-Lymphocyte Subsets, medicine, Immunology and Allergy, Animals, Intestinal Mucosa, Proto-Oncogene Proteins c-vav, Thymocytes, Kinase, Intracellular Signaling Peptides and Proteins, Epistasis, Genetic, Inflammatory Bowel Diseases, Phenotype, Rats, [SDV] Life Sciences [q-bio], Disease Models, Animal, medicine.anatomical_structure, Mutation, Cytokines, Female, Signal transduction, Rats, Transgenic, Signal Transduction
Abstract

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown–Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.

Published
2015

11. Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response

Author

Nicole Malet, Matthias P. Wymann, Laurent O. Martinez, Natalia F. Smirnova, Emilio Hirsch, Abdelhadi Saoudi, Nathalie Vaillant, Christophe Pedros, Dominique Goudounèche, Alain-Pierre Gadeau, Stéphanie Gayral, Denis Calise, Muriel Laffargue, Gervaise Loirand, Sahar Kassem, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de micro-chirurgie, Laboratoire de Micro Chirurgie, Centre de Microscopie Électronique Appliquée à la Biologie (CMEAB), Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Toulouse Réseau Imagerie-Genotoul ( TRI-Genotoul), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institute of Biochemistry and Genetics, Università degli studi di Torino (UNITO), Adaptation cardiovasculaire à l'ischemie, and Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Neointima, Male, medicine.medical_specialty, Intimal hyperplasia, medicine.medical_treatment, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 030204 cardiovascular system & hematology, Vascular occlusion, Article, Rats, Sprague-Dawley, 03 medical and health sciences, Mice, 0302 clinical medicine, Restenosis, Internal medicine, Quinoxalines, medicine, Immunology and Allergy, CXCL10, Animals, Class Ib Phosphatidylinositol 3-Kinase, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Phosphoinositide-3 Kinase Inhibitors, Mice, Knockout, 0303 health sciences, business.industry, hemic and immune systems, Hyperplasia, Th1 Cells, medicine.disease, Arterial occlusion, 3. Good health, Surgery, Rats, Femoral Artery, Mice, Inbred C57BL, Endocrinology, Cytokine, Gene Targeting, Thiazolidinediones, medicine.symptom, Inflammation Mediators, business, Carotid Artery Injuries
Abstract

PI3Kγ plays a major role in the initiation and progression of intimal hyperplasia by specifically modulating Th1 cytokines leading to CXCL10 and RANTES production by smooth muscle cells., Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4+ T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4+ T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.

Published
2014

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