Control of regulatory T cell homeostasis and function by the TH1

免疫介导的炎症性疾病是一个主要的公共卫生问题。在肺部，这些可以是 由暴露于环境中的抗原和毒素或感染引发，并可导致严重的 呼吸道疾病和死亡。定义正常情况下用于预防的免疫调节机制 因此，肺部炎症是理解这些疾病的病因学的关键， 治疗策略来提高患者的这些活性。调节性T细胞（TR）表达 转录因子Foxp 3在预防自身免疫和限制免疫介导的免疫应答中起重要作用， 炎症我们已经表明，在1型炎症反应期间，Foxp 3 + TR上调Thl特异性表达， 转录因子Tbx 21（T-bet），而T-bet表达对于TR的正常稳态至关重要 并在Th介导的炎症过程中发挥作用。因此，本提案的目标是确定 详细描述了Foxp 3 + TR内T-bet的丢失如何影响 在体内急性和持续性肺部感染模型中的这种应答（具体目标1）定义了细胞因子 以及指导T-bet（特异性目标2）TR表达的细胞信号，并在分子水平上进行分析 FoxpS和T-bet如何联合收割机控制参与JhlfTR分化的基因的表达， 稳态和功能（具体目标3）。这些实验将产生前所未有的 了解TR亚群在1型炎症中的分子特化，并提供新的 一个框架，在其中了解所谓的“主转录因子”如何指导功能 CD 4 + 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.