Corepressors in regulatory T cell development and function

项目摘要 调节性T细胞(Tregs)在抑制感染后的免疫反应和 抑制自体反应细胞。树突状细胞缺陷与某些自身免疫疾病的发病机制有关 条件。虽然人们对单个转录因子在调节Treg生物学中的作用知之甚少， 这些转录因子在Tregs表观遗传调控中的作用在很大程度上尚不清楚。 Treg促进转录因子包括FOXP3、STAT5和Smad2/3-Smad4。这些转录 促进Treg特异性基因表达的因子和与其他T辅助细胞亚群相关的沉默基因。这个 它们正向和负向调控基因转录的确切机制尚不清楚。 转录因子可以与辅阻遏物结合，然后将组蛋白脱乙酰基酶募集到 DNA结合。由此产生的组蛋白去乙酰化降低了基因转录。Foxp3、STAT5和SMAD 都与辅阻遏子蛋白NCOR1和NCOR2/SMRT相关。这些交互作用表明 NCOR1/2在调节Tregs中的作用从NCOR1/2缺陷小鼠获得的初步数据表明 包括Tregs在内的所有CD4T细胞都存在严重的数量缺陷。NCOR1/2缺陷小鼠也受到损害 胸腺Treg的发育和从幼稚的CD4T细胞向Treg的分化减少。的影响 Tregs上的NCOR1/2缺失概括了在STAT5缺陷小鼠中观察到的表型。我假设 促Treg转录因子与NCOR1/2促进正常Treg的关系 通过控制表观遗传修饰的发育和功能。我的假设将通过以下方式进行检验 追求以下目标：(1)确定NCOR1/2对Treg分化和功能的贡献以及 (2)确定转录因子-NCOR1/2复合体对Tregs表观遗传格局的贡献。 这些研究的完成将揭示表观遗传修饰在Treg中的作用的重要信息 分化和内稳态。它还将为开发提高Treg数量的疗法提供洞察力 并在自身免疫性疾病中发挥功能和恢复免疫耐受。

PROJECT ABSTRACT Regulatory T cells (Tregs) are critical in dampening the immune response following an infection and suppressing autoreactive cells. Defects in Tregs contribute to disease pathogenesis in some autoimmune conditions. While much is known about the roles of individual transcription factors in regulating Treg biology, the involvement of these transcription factors in the epigenetic regulation of Tregs remains largely unexplored. Treg-promoting transcription factors include FOXP3, STAT5, and SMAD2/3-SMAD4. These transcription factors promote Treg-specific gene expression and silence genes associated with other T helper subsets. The precise mechanism through which they positively and negatively regulate gene transcription remains unclear. Transcription factors can associate with corepressors, which then recruit histone deacetylases to the site of DNA binding. The resulting histone deacetylation decreases gene transcription. FOXP3, STAT5, and SMAD are all known to associate with corepressor proteins NCOR1 and NCOR2/SMRT. These interactions suggest a role for NCOR1/2 in regulating Tregs. Preliminary data obtained from NCOR1/2-deficient mice demonstrate a severe quantitative defect in all CD4 T cells, including Tregs. NCOR1/2-deficient mice also have impaired thymic Treg development and reduced differentiation into Tregs from naïve CD4 T cells. The effects of NCOR1/2 deletion on Tregs recapitulate the phenotype observed in STAT5-deficient mice. I hypothesize that the association of Treg-promoting transcription factors and NCOR1/2 promote normal Treg development and function through control of epigenetic modifications. My hypotheses will be tested by pursuing the following aims: (1) identifying the contribution of NCOR1/2 to Treg differentiation and function and (2) defining the contributions of transcription factor-NCOR1/2 complexes to the epigenetic landscape of Tregs. Completion of these studies will reveal important information about the role of epigenetic modifications in Treg differentiation and homeostasis. It will also provide insight into developing therapies to enhance Treg quantity and function and restore immunological tolerance in autoimmune diseases.