Control of regulatory T cell homeostasis and function by the TH1

免疫介导性炎症性疾病是一个主要的公共卫生问题。在肺部，这些细胞可以是 由暴露于环境因子和毒素或由感染引发，并可导致严重的 呼吸道疾病和死亡。确定正常发挥作用的免疫调节机制，以防止 因此，肺部炎症是了解这些疾病的病因和发展的关键。 治疗策略，以提高这些活动的情侣。调节性T细胞(TR)表达 转录因子Foxp3在预防自身免疫和限制免疫介导中的关键作用 火热的黑手党。我们已经证明，在1型炎症反应中，Foxp3+tr上调Th1指定 转录因子Tbx21(T-bet)，且T-bet表达对于正确的TR动态平衡至关重要 以及在Thi介导的炎症过程中的作用。因此，这项提案的目标是确定 详细说明T-bet的丢失如何影响Foxp3+tr的起始、进展和终止 体内急性和持续性肺部感染模型的THI反应(特异靶1)，确定细胞因子 以及直接表达T-bet的细胞信号(特异靶2)，并在分子水平上进行分析 FoxpS和T-bet如何结合控制JhlfTR差异表达相关基因的表达， 动态平衡和功能(特定目标3)。总而言之，这些实验将产生前所未有的 了解转录因子受体亚群在1型炎症过程中的分子特异性，并提供新的分子生物学机制 理解所谓的“主要转录因子”如何引导功能因子的框架 CD4+T细胞亚群的分化。

Immune-mediated infiammatory diseases are a major public health issue. In the lungs, these can be triggered by exposure to environmental anfigens and toxins, or by infection, and can result in severe respiratory disease and death. Defining the immunoregulatory mechanisms that normally function to prevent pulmonary inflammafion is therefore key to understanding the efiology of these diseases, and for developing therapeutic strategies to boost these acfivities in pafients. Regulatory T cells (TR) expressing the transcripfion factor Foxp3 play a critical role in prevenfing autoimmunity and limifing immune-mediated inflammafion. We have shown that during type-1 inflammatory responses, Foxp3+ TR upregulate the Thlspecifying transcripfion factor Tbx21 (T-bet), and that T-bet expression is crifical for proper TR homeostasis and funcfion during Thi-mediated inflammation. Therefore, the goals of this proposal are to determine in detail how loss of T-bet specifically within Foxp3+ TR impacts the initiafion, progression and terminafion of Thi responses in models of acute and persistent lung infection in vivo (Specific Aim 1), define the cytokines and cellular signals that direct TR expression of T-bet (Specific Aim 2), and analyze at the molecular level how FoxpS and T-bet combine to control the expression of genes involved in JhlfTR differenfiafion, homeostasis and funcfion (Specific Aim 3). Together, these experiments will generate an unprecedented understanding of the molecular specializafion of TR subsets during type-1 inflammafion, and provide a new framework in which to understand how so-called 'master transcription factors' direct the funcfional differenfiation of CD4+ T cell subsets.