Role of Negative Regulation in Development of Diabetes

描述（由申请人提供）： 最近的证据表明，幼稚外周T细胞的存活是一个活跃的过程，需要T细胞受体与由负责胸腺选择的相同MHC分子呈递的自身肽相互作用。然而，这种T细胞受体与自身MHC的相互作用不会导致T细胞活化，因为该过程被活化的负调节因子家族抑制。我们小组最近的工作表明，错误的负调节可能允许激活自身反应性T细胞，并且在自身免疫易感动物中T细胞受体信号传导的内在低反应性可能进一步增强负调节的任何缺陷。总之，这些条件可以导致外周自身反应性T细胞的富集，并最终引发自身免疫性疾病。该应用将加强两个实验室之间的合作，这两个实验室在细胞周期调控和I型糖尿病免疫生物学方面具有专长。所提出的实验被设计为检验以下假设：（1）除非T细胞接收到强的存活信号，否则负调节的失败导致细胞周期进入和死亡的失败，以及（2）由于T细胞受体信号传导中的内在低反应性，负调节的失败优先允许自身反应性克隆的扩增，从而导致自身免疫。

DESCRIPTION (provided by applicant): Recent evidence indicates that survival of naive peripheral T cells is an active process requiring the interaction of the T cell receptor with self-peptides presented by the same MHC molecules that are responsible for thymic selection. However this T cell receptor interaction with self MHC does not lead to T cell activation because this process is dampened by a family of negative regulators of activation. Recent work from our group indicates that faulty negative regulation may permit the activation of autoreactive T cells, and that intrinsic hyporesponsiveness of T cell receptor signaling in autoimmune prone animals may further enhance any deficiency in negative regulation. Together, these conditions can lead to enrichment of peripheral autoreactive T cells and ultimately instigate autoimmune disease. This application will reinforce a collaboration between two laboratories with expertise in cell cycle regulation and the immunbiology of Type I diabetes. The experiments proposed are designed to test the hypotheses that (1) failure of negative regulation leads to abortive cell cycle entry and death unless the T cells receive a strong survival signal and (2) because of an intrinsic hyporesponsiveness in T cell receptor signaling the failure of negative regulation preferentially permits the expansion of autoreactive clones resulting in autoimmunity.