Functional specialization of Foxp3+ regulatory T cells

免疫介导的自身免疫性和炎症性疾病是一个主要的公共卫生问题。定义 因此，正常起作用以预防肺部炎症的调节机制是关键。 了解这些疾病的病因，并制定治疗策略，以促进 患者的这些活动。表达转录因子Foxp3的调节性T细胞发挥作用 在预防自身免疫和限制免疫介导性炎症方面的关键作用。我们已经展示了 在1型炎症反应中，Foxp3+上调Th1特异性转录 因子Tbx21(T-bet)，且T-bet表达对于正确的TR动态平衡和功能至关重要 在Th1介导的炎症过程中。因此，这项提案的目标是详细确定 Foxp3+tR内T-bet的丢失如何影响Foxp3+TR的启动、进展和终止 Th1在体内的反应(特定目标1)；在分子水平上分析Foxp3和T-bet是如何结合的 调控Th1/TR分化、动态平衡和功能相关基因的表达 (具体目标2)；以及确定控制表型和细胞信号的细胞因子和细胞信号 不同受体亚群的功能分化(具体目标3)。

Immune-mediated autoimmune and inflammatory diseases are a major public health issue. Defining the regulatory mechanisms that normally function to prevent pulmonary inflammation is therefore key to understanding the etiology of these diseases, and for developing therapeutic strategies to boost these activities in patients. Regulatory T cells (TR) expressing the transcription factor Foxp3 play a critical role in preventing autoimmunity and limiting immune-mediated inflammation. We have shown that during type-1 inflammatory responses, Foxp3+ TR upregulate the Th1-specifying transcription factor Tbx21 (T-bet), and that T-bet expression is critical for proper TR homeostasis and function during Th1-mediated inflammation. Therefore, the goals of this proposal are to determine in detail how loss of T-bet specifically within Foxp3+ TR impacts the initiation, progression and termination of Th1 responses in vivo (Specific Aim 1); analyze at the molecular level how Foxp3 and T-bet combine to control the expression of genes involved in Th1/TR differentiation, homeostasis and function (Specific Aim 2); and to identify the cytokines and cellular signals that control the phenotypic and functional differentiation of different TR subsets (Specific Aim 3).