New T Cell Coinhibitory Pathway and Type 1 Diabetes

免疫学 T淋巴细胞是获得性免疫的中枢介质，发挥着关键作用。 在两种适当的免疫反应中都发挥作用(如免疫 病原体)和异常(如导致类型的自身免疫反应 1例糖尿病)。最佳的激活、增殖和分化为效应器 T细胞的功能需要同时出现两个信号：抗原 通过T细胞抗原受体的特定信号和附加的共刺激信号 (共刺激)主要由B7和CD28之间的相互作用产生 家人。为了解B7-1的T细胞共刺激作用所做的巨大努力， 在过去的十年中，B7-2/CD28，CTLA-4通路在很大程度上塑造了我们的 对免疫系统和免疫相关疾病的了解，如 为1型糖尿病。我们发现了B7家族的最新成员， B7x，能够在体外抑制T细胞功能(共抑制)。然而， B7x在糖尿病中的作用尚不清楚。有趣的是，我们最近发现， 与B7-1和B7-2不同，人类和小鼠的B7x基因都位于胰岛素中- 依赖的糖尿病基因，并在胰岛表达。此外，我们 发现在胰腺细胞中过度表达B7x的转基因小鼠 抵抗CD4T细胞介导的1型糖尿病。根据初步数据， 我们假设B7x代表一种新的T细胞共抑制途径 这会削弱胰腺中的效应器T细胞功能。我们已经生成了一个数字 重要工具(mAbto B7x、B7x转基因小鼠、B7x基因敲除小鼠等) 这为我们提供了独特的机会来分析B7x途径在 1型糖尿病。总体而言，对该项目的研究不仅可以促进我们的 对1型糖尿病及其致病过程的认识 但也导致了一种合理的临床治疗方法 干预。

Immunology T lymphocytes are central mediators of adaptive immunity, playing a key role in both appropriate immune responses (such as immunity against pathogens) and abnormal ones (such as autoimmune response that lead to type 1 diabetes). Optimal activation, proliferation, and differentiation to effector function of T cells require a simultaneous occurrence of two signals: antigen specific signals via T cell antigen receptors, and additional costimulatory signals (costimulation) generated mainly by the interaction between the B7 and CD28 families. The intense effort towards understanding T cell costimulation of B7-1, B7-2/CD28, CTLA-4 pathway over the past decade has shaped much of our understanding regarding the immune system and immune-related diseases such as type 1 diabetes. We have discovered the newest member of the B7 family, B7x, which is capable of inhibiting T cell function in vitro (coinhibition). However, the role of B7x in diabetes is unknown. Interestingly, we have recently found that, unlike B7-1 and B7-2, both human and mouse B7x genes are located in insulin- dependent diabetes loci and are expressed in pancreatic islets. Moreover, we have found that transgenic mice overexpressing B7x in pancreatic ¿ cells are resistant to CD4 T cell mediated type 1 diabetes. Based on the preliminary data, we have hypothesized that B7x represents a novel T cell coinhibitory pathway that attenuates effector T cell function in pancreas. We have generated a number of important tools (mAbs to B7x, B7x transgenic mice, B7x knock-out mice, etc.) that provide us with unique opportunities to analyze the role of B7x pathway in type 1 diabetes. Overall, the studies of this project may not only advance our understanding of the pathogenic processes underlying type 1 diabetes and its complicatios but also lead to a rational approach for clinical therapeutic intervention.