Cancer Research Center of Lyon, UMR INSERM 1052, CNRS 5286, Lyon, France Université Lyon 1, Lyon, France Centre Léon Bérard, Lyon, France.
National Institute of Diabetes, Nutrition and Metabolic Diseases "N. Paulescu," Bucharest, Romania.
Diabetes. 2015 Dec;64(12):4212-9. doi: 10.2337/db15-0638. Epub 2015 Oct 15.
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.
βig-h3/TGF-βi 是一种分泌蛋白，能够与细胞外基质和细胞结合。人类遗传学研究最近表明，在编码 βig-h3 的 tgfbi 基因中，三个单核苷酸多态性与 1 型糖尿病（T1D）风险显著相关。在生理条件下，胰岛表达βig-h3，但在 T1D 中β细胞损伤时表达减少。由于胰岛的完整性被自身免疫性 T 淋巴细胞破坏，我们考虑研究βig-h3 对 T 细胞活化的影响。我们在这里表明，βig-h3 抑制 T 细胞活化标志物以及细胞毒性分子的产生，如颗粒酶 B 和 IFN-γ。此外，βig-h3 通过抑制早期激酶蛋白 Lck 的激活来抑制早期 T 细胞受体信号转导。此外，在用 Rag2 基因敲除小鼠进行转移时，βig-h3 处理的 T 细胞无法诱导 T1D。我们的研究首次表明，T 细胞的活化受到胰岛细胞外蛋白βig-h3 的调节，以有效地避免自身免疫反应。
