TCR gamma delta intraepithelial lymphocytes are required for self-tolerance.
TCR gamma delta intraepithelial lymphocytes are required for self-tolerance.
复制标题
TCR γ δ 上皮内淋巴细胞是自我耐受所必需的。
作者：
Natasha R. Locke;S. Stanković;D. Funda;L. Harrison
新生儿胸腺切除(NTX)损害T细胞调节，并导致易感小鼠的器官特异性自身免疫病。在自发性1型糖尿病的NOD小鼠模型中，我们观察到NTX显著加速了自身免疫性胰岛β细胞的破坏和糖尿病。在通过在APC中转基因表达β细胞自身抗原胰岛素原而受到保护的NOD小鼠中，NTX只有很小的影响，推测NTX后糖尿病的加速主要是由于未能调节胰岛素原特异性T细胞。NTX显著损害上皮内淋巴细胞(IEL)的发育，与对照品系相比，NOD小鼠的IEL数量已经减少。从NOD小鼠体内提纯的IEL，特别是CD8αTCRGammadelta IEL，当被转移到NTX-NOD小鼠体内时，被输送到小肠上皮细胞，从而预防糖尿病。转移原型的CD4+CD25+调节性T细胞也可以预防NTX-NOD小鼠的糖尿病；然而，口服胰岛素在胸腺好的小鼠中诱导这些细胞取决于TCRGammadelta IEL的完整性。我们得出结论，位于自我和非我之间粘膜界面的TCRGammadelta IEL在维持外周耐受方面发挥着关键作用，无论是生理上的还是在口服耐受诱导过程中都是如此。
Neonatal thymectomy (NTX) impairs T cell regulation and leads to organ-specific autoimmune disease in susceptible mouse strains. In the NOD mouse model of spontaneous type 1 diabetes, we observed that NTX dramatically accelerated autoimmune pancreatic beta cell destruction and diabetes. NTX had only a minor effect in NOD mice protected from diabetes by transgenic expression of the beta cell autoantigen proinsulin in APCs, inferring that accelerated diabetes after NTX is largely due to failure to regulate proinsulin-specific T cells. NTX markedly impaired the development of intraepithelial lymphocytes (IEL), the number of which was already reduced in euthymic NOD mice compared with control strains. IEL purified from euthymic NOD mice, specifically CD8alphaalpha TCRgammadelta IEL, when transferred into NTX-NOD mice, trafficked to the small intestinal epithelium and prevented diabetes. Transfer of prototypic CD4+CD25+ regulatory T cells also prevented diabetes in NTX-NOD mice; however, the induction of these cells by oral insulin in euthymic mice depended on the integrity of TCRgammadelta IEL. We conclude that TCRgammadelta IEL at the mucosal interface between self and nonself play a key role in maintaining peripheral tolerance both physiologically and during oral tolerance induction.