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，确定正常情况下预防肺部炎症的调节机制是了解这些疾病的病因并制定治疗策略以促进患者这些活动的关键。表达转录因子Foxp3的调节性T细胞在预防自身免疫和限制免疫介导的炎症中起着关键作用。我们已经证明，在1型炎症反应中，Foxp3+tr上调Th1特定的转录因子Tbx21(T-bet)，并且T-bet的表达对于Th1介导的炎症过程中正确的TR动态平衡和功能至关重要。因此，这项建议的目标是详细地确定在Foxp3+TR中特异性的T-bet缺失如何影响体内Th1反应的启动、进展和终止(特定目标1)；在分子水平上分析Foxp3和T-bet如何结合来控制Th1/TR分化、稳态和功能相关基因的表达(特定目标2)；以及确定控制不同TR亚群的表型和功能分化的细胞因子和细胞信号(特定目标3)。 公共卫生相关性：了解调节性T细胞如何调节Th1和Th17介导的免疫反应在这些细胞的临床应用中具有明确和直接的意义，这些细胞用于治疗由调节失调的Th1细胞反应引起的免疫介导性炎症和自身免疫性疾病，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、牛皮癣、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.