title: βig-h3 Represses T-Cell Activation in Type 1 Diabetes.
abstract: βig-h3/TGF-βi is a secreted protein capable of binding to both extracellular matrix and cells. Human genetic studies recently revealed that in the tgfbi gene encoding for βig-h3, three single nucleotide polymorphisms were significantly associated with type 1 diabetes (T1D) risk. Pancreatic islets express βig-h3 in physiological conditions, but this expression is reduced in β-cell insult in T1D. Since the integrity of islets is destroyed by autoimmune T lymphocytes, we thought to investigate the impact of βig-h3 on T-cell activation. We show here that βig-h3 inhibits T-cell activation markers as well as cytotoxic molecule production as granzyme B and IFN-γ. Furthermore, βig-h3 inhibits early T-cell receptor signaling by repressing the activation of the early kinase protein Lck. Moreover, βig-h3-treated T cells are unable to induce T1D upon transfer in Rag2 knockout mice. Our study demonstrates for the first time that T-cell activation is modulated by βig-h3, an islet extracellular protein, in order to efficiently avoid autoimmune response.
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
authors.forename: Maeva
authors.initials: M
authors.lastname: Patry
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Teinturier
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Goehrig
authors.affiliation: National Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu," Bucharest, Romania.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zetu
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
authors.forename: Doriane
authors.initials: D
authors.lastname: Ripoche
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bertolino
authors.affiliation: Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France ana.hennino@inserm.fr.
authors.forename: Ana
authors.initials: A
authors.lastname: Hennino
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002102:Cadaver; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000099222:betaIG-H3 Protein
chemical_list: D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D007004:Hypoglycemic Agents; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D047428:Protein Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein