iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes

据报道，CD 1d限制性T细胞（或“iNKT细胞”）调节一组极其多样的免疫调节因子。 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显然是 与自身免疫性，特别是自身免疫性1型糖尿病的发展相关。尽管 CDId限制性T细胞在这种疾病中的重要性，这些T细胞如何正常发挥功能的问题， 疾病相关缺陷的确切性质仍不清楚。在这方面，潜在的监管 预测对1型糖尿病具有显著影响的功能包括最近描述的 CDId限制性T细胞与树突状细胞（DC;项目2的重点）的关键相互作用， 活化诱导的调节性细胞因子的分泌。最近的研究表明，在正常人中， 在志愿者中，CD 4 + CDId限制性亚群优先分泌调节性细胞因子，而CD 4- (or DM）亚群强烈偏向于Th 1相关细胞因子的分泌，并且表达更高。 具有细胞毒性功能的蛋白质水平。我们已经观察到，有1型糖尿病风险的个体有 显著偏向DN亚群。也许更重要的是，CD 4 + iNKT细胞优先表达 FOXP 3（项目3的焦点），并分泌一种尚未鉴定的诱导髓样DC的因子 分化有趣的是，FOXP 3的表达依赖于IL-2和CD 25，这两者都是 候选1型糖尿病易感等位基因。因此，CD 4 + CD 1d限制性T细胞可能有助于预防 通过控制DC成熟和效应T细胞而DN CDId限制性T细胞 可能会促进炎症反应。在本提案中，我们计划调查项目2和3， CD 4+和DN iNKT细胞相互作用并调节T效应细胞和APC的机制。为此， 我们的建议将专门检验CD 4 + iNKT细胞是一类独特的调节性T细胞的假设 并可能有助于防止进展为自身免疫性1型糖尿病，而DN iNKT细胞发挥更多的作用， 致病作用这一假设预测，与对照组相比，CD 4 + iNKT细胞亚群的活性降低， DN亚群（可能是由于CD 4+功能的选择性缺陷，或DN与 CD 4+比例），在某些情况下可能与进展为1型糖尿病有关。这一假设 将通过两个具体目标的性能进行测试，包括：1）iNKT频率和功能的分析， 和2）由CD 4 + iNKT细胞分泌的DC分化因子的表征。与项目2 第三，这些研究的成功完成可以提高对 导致1型糖尿病的自身免疫活动的机制以及 识别对免疫调节重要的新因子。

CD1d-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 type 1 diabetes. Despite the importance of CDId-restricted T cells in this disease, the question of 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 CDId-restricted T cells with dendritic cells (DC; the focus of Project 2) and the activation-induced secretion of regulatory cytokines. Recent work has demonstrated that in normal human volunteers, the CD4+ CDId-restricted subset preferentially secrete regulatory cytokines, whereas the CD4- (or "DM") subset were strongly biased towards the secretion of Th1-related cytokines and expressed greater levels of proteins with cytotoxic function. We have observed that individuals at risk for type 1 diabetes have a significant bias towards the DN subset. Perhaps more importantly, CD4+ iNKT cells preferentially express FOXP3 (the focus of Project 3) and secrete an as of yet to be identified factor that induces myeloid DC differentiation. Interestingly, the expression of FOXP3 is dependent on IL-2 and CD25, both of which are candidate type 1 diabetes susceptibility alleles. Thus, CD4+ CD1 d-restricted T cells might serve to prevent progression to diabetes by controlling DC maturation and effector T cells while DN CDId-restricted T cells might promote pro-inflammatory responses. In this proposal, we plan to investigate with Projects 2 and 3, the mechanism by which CD4+ and DN iNKT cells interact and regulate T effector cells and APC. To that end, our proposal will specifically test the hypothesis that CD4+ iNKT cells are a unique class of regulatory T cells and may serve to prevent progression to autoimmune type 1 diabetes, while DN iNKT cells play a more pathogenic role. This hypothesis predicts that reduced activity of the CD4+ iNKT cell subset compared to that of the DN subset (which could result from a selective defect in CD4+ functions, or an alteration in DN vs. CD4+ proportion), could in some cases be associated with progression to type 1 diabetes. This hypothesis will be tested by performance of two specific aims involving: 1) Analyses of iNKT frequency and function, and 2) Characterization of DC differentiation factor(s) secreted by CD4+ iNKT cells. Together with Projects 2 and 3, the successful completion of these studies could lead to an improved understanding of the mechanisms underlying the autoimmune activity that that results in type 1 diabetes as well as the identification of novel factors important to immune regulation.