βig-h3 Represses T-Cell Activation in Type 1 Diabetes

Maeva Patry; Romain Teinturier; Delphine Goehrig; Cornelia Zetu; Doriane Ripoche; In-San Kim; Philippe Bertolino; Ana Hennino

doi:10.2337/db15-0638

βig-h3 Represses T-Cell Activation in Type 1 Diabetes

Diabetes. 2015 Dec;64(12):4212-9. doi: 10.2337/db15-0638. Epub 2015 Oct 15.

Authors

Maeva Patry¹, Romain Teinturier¹, Delphine Goehrig¹, Cornelia Zetu², Doriane Ripoche¹, In-San Kim³, Philippe Bertolino¹, Ana Hennino⁴

Affiliations

¹ Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
² National Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu," Bucharest, Romania.
³ Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Korea KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Korea.
⁴ 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.

PMID: 26470788
DOI: 10.2337/db15-0638

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity / drug effects*
Biomarkers / metabolism
Cadaver
Cells, Cultured
Diabetes Mellitus, Type 1 / drug therapy*
Diabetes Mellitus, Type 1 / immunology
Diabetes Mellitus, Type 1 / metabolism
Diabetes Mellitus, Type 1 / pathology
Diabetes Mellitus, Type 2 / drug therapy
Diabetes Mellitus, Type 2 / immunology
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Extracellular Matrix Proteins / genetics
Extracellular Matrix Proteins / metabolism
Extracellular Matrix Proteins / pharmacology*
Female
Humans
Hypoglycemic Agents / metabolism
Hypoglycemic Agents / pharmacology*
Lymph Nodes / pathology
Lymphocyte Activation / drug effects*
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Receptors, Antigen, T-Cell / antagonists & inhibitors
Receptors, Antigen, T-Cell / metabolism
Recombinant Proteins / metabolism
Recombinant Proteins / pharmacology
Recombinant Proteins / therapeutic use
Signal Transduction / drug effects*
Specific Pathogen-Free Organisms
T-Lymphocytes / drug effects*
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta / pharmacology*

Substances

Biomarkers
Extracellular Matrix Proteins
Hypoglycemic Agents
Protein Kinase Inhibitors
Receptors, Antigen, T-Cell
Recombinant Proteins
Transforming Growth Factor beta
betaIG-H3 protein
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)