Role of Negative Regulation in Development of Diabetes

描述(由申请人提供)： 最近的证据表明，原始外周T细胞的存活是一个活跃的过程，需要T细胞受体与负责胸腺选择的同一MHC分子提供的自体多肽相互作用。然而，这种T细胞受体与自身MHC的相互作用不会导致T细胞的激活，因为这一过程被一系列负的激活调节因子所抑制。我们课题组最近的工作表明，错误的负调控可能允许自身反应性T细胞的激活，而自身免疫倾向动物中T细胞受体信号的固有低反应性可能进一步增强负调控的任何缺陷。总而言之，这些情况会导致外周自身反应性T细胞的丰富，最终引发自身免疫性疾病。这项应用将加强两个拥有细胞周期调节和I型糖尿病免疫生物学专业知识的实验室之间的合作。这些实验旨在验证以下假设：(1)除非T细胞收到强烈的生存信号，否则负调控的失败会导致细胞周期进入和死亡的流产；(2)由于T细胞受体信号传递的内在低反应性，负调控的失败优先允许自身反应性克隆的扩张，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.