Regulation of iNKT and APC Interactions

描述(由申请人提供)：CD ID限制性T细胞(或“iNKT细胞”)已被报道调节一组极其不同的免疫反应和疾病。包括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生明显相关。尽管CD ID限制性T细胞在这种疾病中很重要，但这些T细胞是如何正常发挥作用的，以及与疾病相关的缺陷的确切性质仍不清楚。在这方面，预测对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Th1和Th2细胞因子的分泌。在小鼠模型中，CD ID限制性T细胞分泌Th2细胞因子与预防自身免疫性糖尿病有关。相反，从1型糖尿病患者中克隆的CD ID限制性T细胞被发现具有极端的Th1细胞因子偏向等缺陷。最近的研究表明，在正常人中，CD4ID受限的亚群负责体内Th2细胞因子的产生，而CD4-(或“DN”)亚群强烈偏向于Th1细胞因子的分泌，并表达更多具有细胞毒功能的蛋白质。最近，我们发现1型糖尿病高危人群的糖尿病肾病亚组显著增加。重要的是，我们还确定了由CD4而不是由dN iNKT细胞分泌的积极调节DC分化的因子。髓系树突状细胞的成熟缺陷被认为是与糖尿病风险相关的一种重要的细胞缺陷。因此，CD4iNKT细胞可能有助于防止糖尿病的进展，而糖尿病肾病iNKT细胞可能促进促炎反应。为了检验这两个亚组不同效应器功能的假设，我们建议在以下特定目标中比较糖尿病患者、高危捐赠者和对照捐赠者： 目的1.分析CDLD限制性T细胞的频率和功能。 目的2.CD4iNKT细胞分泌的树突状细胞分化因子S的特性 目的3.对APC依赖的免疫突触激活和形成过程中共受体功能的分子分析。

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.