iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes

据报道，CD1d 限制性 T 细胞（或“iNKT 细胞”）可调节极其多样化的细胞 免疫反应和疾病。这些 T 细胞的功能障碍（包括细胞因子分泌）显然是 与自身免疫的发展相关，特别是自身免疫1型糖尿病。尽管 CDId 限制性 T 细胞在这种疾病中的重要性、这些 T 细胞如何正常发挥作用的问题以及 与疾病相关的缺陷的确切性质仍不清楚。在这方面，潜在的监管 预计会对 1 型糖尿病产生重大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）的关键相互作用以及 激活诱导调节性细胞因子的分泌。最近的工作表明，在正常人类中 在志愿者中，CD4 CDId 限制亚群优先分泌调节细胞因子，而 CD4- （或“DM”）子集强烈偏向于 Th1 相关细胞因子的分泌，并且表达量更大 具有细胞毒功能的蛋白质水平。我们观察到，有 1 型糖尿病风险的个体有 显着偏向 DN 子集。也许更重要的是，CD4 iNKT 细胞优先表达 FOXP3（项目 3 的重点）并分泌一种尚未确定的诱导骨髓 DC 的因子 差异化。有趣的是，FOXP3 的表达依赖于 IL-2 和 CD25，两者都是 候选 1 型糖尿病易感性等位基因。因此，CD4 CD1 d 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细胞进展为糖尿病 可能促进促炎症反应。在本提案中，我们计划通过项目 2 和 3 进行调查， CD4 和 DN iNKT 细胞相互作用并调节 T 效应细胞和 APC 的机制。为此， 我们的提案将专门测试 CD4 iNKT 细胞是一类独特的调节性 T 细胞的假设 并可能有助于预防进展为自身免疫 1 型糖尿病，而 DN iNKT 细胞则发挥更重要的作用 致病作用。该假设预测，与其他细胞相比，CD4 iNKT 细胞亚群的活性降低 DN 子集（这可能是由于 CD4 功能的选择性缺陷，或 DN 与 DNA 的改变所致） CD4 比例），在某些情况下可能与 1 型糖尿病的进展有关。这个假设 将通过两个具体目标的表现进行测试，包括：1) iNKT 频率和功能分析， 2) CD4 iNKT 细胞分泌的 DC 分化因子的表征。与项目 2 一起 3、成功完成这些研究可以加深对 导致 1 型糖尿病的自身免疫活动的潜在机制以及 鉴定对免疫调节重要的新因素。

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.