Functional specialization of Foxp3+ regulatory T cells

描述（由申请人提供）：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。因此，定义通常用于预防肺部炎症的调节机制是理解这些疾病病因的关键，也是开发治疗策略以促进患者这些活动的关键。表达转录因子Foxp 3的调节性T细胞（TR）在预防自身免疫和限制免疫介导的炎症中起关键作用。我们已经表明，在1型炎症反应，Foxp 3 + TR上调Th 1特异性转录因子Tbx 21（T-bet），和T-bet的表达是至关重要的适当TR稳态和功能在Th 1介导的炎症。因此，本提案的目标是详细确定Foxp 3 + TR内特异性T-bet的缺失如何影响体内Th 1应答的起始、进展和终止（具体目标1）;在分子水平上分析Foxp 3和T-bet如何结合联合收割机来控制参与Th 1/TR分化、稳态和功能的基因的表达（具体目标2）;以及鉴定控制不同TR亚群的表型和功能分化的细胞因子和细胞信号（具体目标3）。 公共卫生相关性：了解调节性T细胞如何调节Th 1和Th 17介导的免疫应答，对于这些细胞用于治疗由Th 1细胞应答失调引起的免疫介导的炎症和自身免疫性疾病的临床应用具有明确和直接的意义，所述疾病例如与持续性结核分枝杆菌感染相关的肉芽肿性炎症、过敏性肺炎、银屑病、类风湿性关节炎、1型糖尿病和多发性硬化症

DESCRIPTION (provided by applicant): 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 a 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). PUBLIC HEALTH RELEVANCE: Understanding how regulatory T cells modulate Th1- and Th17mediated immune responses has clear and direct implications in the clinical application of these cells for the treatment of immune-mediated inflammatory and autoimmune diseases caused by dysregulated Th1 cell responses, such as granulomatous inflammation associated with persistent Mycobacterium tuberculosis infection, hypersensitivity pneumonitis, psoriasis, rheumatoid arthritis, type-1 diabetes and multiple sclerosis.