Regulation of iNKT and APC Interactions

iNKT 和 APC 相互作用的调节

• 批准号: 6924996
• 负责人: S. Brian BRIAN Wilson
• 金额: $ 29.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924996
• 关键词: Regulation; iNKT; APC; Interactions

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.

描述（由申请人提供）：已报道CD Id限制性T细胞（或“iNKT细胞”）调节极其多样化的一组免疫应答和疾病。这些T细胞的包括细胞因子分泌在内的功能障碍显然与自身免疫的发展相关，特别是与自身免疫性糖尿病相关。尽管CD Id限制性T细胞在这种疾病中的重要性，但这些T细胞如何正常发挥功能以及疾病相关缺陷的确切性质仍不清楚。在这方面，预测对1型糖尿病具有显著影响的潜在调节功能包括最近描述的CD Id限制性T细胞与树突细胞的关键相互作用以及Thl和Th 2细胞因子的活化诱导的分泌。在鼠模型中，CDld限制性T细胞的Th 2细胞因子分泌与自身免疫性糖尿病的保护相关。相反，发现从1型糖尿病患者克隆的CD Id限制性T细胞，除其他缺陷外，具有极端的Thl细胞因子偏倚。最近的工作已经证明，在正常人志愿者中，CD 4 + CD Id限制性亚群负责体内Th 2细胞因子的产生，而CD 4-（或“DN”）亚群强烈偏向于Th 1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1型糖尿病风险人群的DN亚群显著增加。重要的是，我们还鉴定了由CD 4+细胞分泌而不是由DN iNKT细胞分泌的因子，其正调节DC分化。髓样DC的成熟缺陷被认为是与糖尿病风险相关的显著细胞缺陷。因此，CD 4 + 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。为了检验这两个亚群的不同效应子功能的假设，我们建议在以下具体目标中比较糖尿病患者、风险供体和对照供体： 目标1. CDld限制性T细胞频率和功能分析。 目标2. CD 4 + iNKT细胞分泌的树突状细胞分化因子的表征 目标3。APC依赖性激活和免疫突触形成期间辅助受体功能需求的分子分析。