Regulation of iNKT and APC Interactions

描述（由申请人提供）：据报道，cdid限制性T细胞（或“iNKT细胞”）调节极其多样化的免疫反应和疾病。包括这些T细胞分泌细胞因子在内的功能障碍与自身免疫，特别是自身免疫性糖尿病的发展明显相关。尽管CD id限制性T细胞在这种疾病中的重要性，但这些T细胞如何正常发挥作用以及疾病相关缺陷的确切性质尚不清楚。在这方面，预计对1型糖尿病有重大影响的潜在调节功能包括最近描述的CD id限制性T细胞与树突状细胞的关键相互作用以及激活诱导的Thl和Th2细胞因子的分泌。在小鼠模型中，cdid限制性T细胞分泌Th2细胞因子与保护自身免疫性糖尿病有关。相反，从1型糖尿病患者身上克隆的CD id限制性T细胞，除了其他缺陷外，还被发现具有极端的Thl细胞因子偏倚。最近的研究表明，在正常的人类志愿者中，CD4+ CD id限制亚群负责体内Th2细胞因子的产生，而CD4-（或“DN”）亚群强烈倾向于Thl细胞因子的分泌，并表达更高水平的具有细胞毒性功能的蛋白质。最近我们发现，有患1型糖尿病风险的人的DN亚群显著增加。重要的是，我们还发现了由CD4+分泌的因子，而不是由DN iNKT细胞分泌的因子，它们积极调节DC分化。髓系DC成熟缺陷被认为是与糖尿病风险相关的重要细胞缺陷。因此，CD4+ iNKT细胞可能有助于预防糖尿病的进展，而DN iNKT细胞可能促进促炎反应。为了验证这两个亚群的不同效应函数假设，我们建议比较糖尿病患者、危险供体和对照组供体，具体目的如下：

DESCRIPTION (provided by applicant): CD Id-restricted T cells (or "iNKT cells") have been reported to regulate an extremely diverse set of immunologic responses and diseases. Dysfunction including cytokine secretion by these T cells is clearly correlated with the development of autoimmunity, and in particular autoimmune diabetes. Despite the importance of CD Id-restricted T cells in this disease, how these T cells function normally and the exact nature of the disease-associated defects remains unclear. In this regard, potential regulatory functions that would be predicted to have significant impact on type 1 diabetes include recently described critical interactions of CD Id-restricted T cells with dendritic cells and the activation-induced secretion of Thl and Th2 cytokines. Th2 cytokine secretion by CD Id-restricted T cells has been associated with protection from autoimmune diabetes in murine models. Conversely, CD Id-restricted T cells cloned from patients with type 1 diabetes were found, amongst other defects, to have an extreme Thl cytokine bias. Recent work has demonstrated that in normal human volunteers, the CD4+ CD Id-restricted subset is responsible for Th2 cytokine production in vivo, whereas the CD4- (or "DN") subset were strongly biased towards the secretion of Thl cytokines and expressed greater levels of proteins with cytotoxic function. Recently we found that people at risk for type 1 diabetes have a significant increase in the DN subset. Importantly, we have also identified factors secreted by CD4+ but not by DN iNKT cells that positively regulate DC differentiation. Defective maturation of myeloid DC is thought to be a significant cellular defect related to diabetes risk. Hence, CD4+ iNKT cells might serve to prevent progression to diabetes whilst DN iNKT cells might promote pro-inflammatory responses. To test the hypothesis of distinct effector function for these two subsets we propose to compare diabetes patients, at risk donors, and control donors in the following specific aims: Aim 1. Analyses of CDld-restricted T frequency and function. Aim 2. Characterization of dendritic cell differentiation factor(s) secreted by CD4+ iNKT cells Aim 3. Molecular analysis of the requirements for co-receptor function during APC-dependent activation and formation of the immunologic synapse.