iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes

1 型糖尿病中的 iNKT 细胞基因表达和效应器功能

• 批准号: 7185718
• 负责人: S. Brian BRIAN Wilson
• 金额: $ 33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185718
• 关键词: Address; Alleles; Antigen-Presenting Cells; Antigens; Attention; Autoantigens; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; Cell Differentiation process; Cell physiology; Cells; Class; Clone Cells; Defect; Dendritic Cells; Development; Diabetes Mellitus; Disease; Disease Progression; Disease susceptibility; Effector Cell; Equilibrium; Frequencies; Functional disorder; Gene Expression; Goals; Human; Human Volunteers; IL2RA gene; Immune; Immunologics; In Vitro; Inbred BB Rats; Inbred NOD Mice; Individual; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-2; Interleukin-4; Lead; Modeling; Monoclonal Antibodies; Movement; Mus; Myelogenous; Nature; Pathogenesis; Patients; Pattern; Phenotype; Phosphorylation; Play; Predisposition; Process; Production; Proteins; Regulation; Reporting; Research Personnel; Risk; Rodent Model; Role; Signal Transduction; Specificity; Susceptibility Gene; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; To autoantigen; Work; autoreactive T cell; base; cell type; cytokine; cytotoxic; disease natural history; human subject; improved; novel; performance tests; prevent; response

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.

据报道，CD1d限制性T细胞(或称iNKT细胞)调节一组极其不同的 免疫反应和疾病。这些T细胞的功能障碍包括分泌细胞因子显然是 与自身免疫性疾病，特别是自身免疫性1型糖尿病的发展有关。尽管 CDID限制性T细胞在本病中的重要性，这些T细胞如何正常发挥作用以及 与疾病相关的缺陷的确切性质尚不清楚。在这方面，潜在的监管 预测会对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的焦点)的关键相互作用 激活诱导调节性细胞因子的分泌。最近的研究表明，在正常的人类中 在志愿者中，受CD4+CDID限制的亚群优先分泌调节性细胞因子，而CD4-CDID限制的亚群 (或“DM”)亚群强烈偏向于Th1相关细胞因子的分泌，并表达更多 具有细胞毒功能的蛋白质水平。我们观察到，有1型糖尿病风险的人有 对目录号码子集的显著偏向。也许更重要的是，CD4+iNKT细胞优先表达 Foxp3(项目3的焦点)，并分泌一种尚未确定的诱导髓系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型糖尿病易感等位基因。因此，CD4+CD1d限制性T细胞可能起到预防 通过控制DC成熟和效应T细胞进展为糖尿病，而DNCDID限制T细胞 可能会促进促炎反应。在这项提案中，我们计划与项目2和3一起调查 CD4+和dN iNKT细胞相互作用和调节T效应细胞和APC的机制。为此， 我们的建议将专门检验这一假设，即CD4+iNKT细胞是一种独特的调节性T细胞 可能有助于防止进展为自身免疫性1型糖尿病，而糖尿病肾病iNKT细胞则发挥更大的作用 致病作用。这一假设预测，与CD+iNKT细胞亚群相比， 糖尿病肾病亚集(这可能是由于CD4+功能的选择性缺陷，或糖尿病肾病与 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表现进行测试，包括：1)分析iNKT的频率和功能， 2)CD_4~+iNKT细胞分泌的DC分化因子(S)的鉴定。与项目2一起 3、这些研究的成功完成可能会提高人们对 导致1型糖尿病的自身免疫活动的潜在机制以及 识别对免疫调节重要的新因素。