Corepressors in regulatory T cell development and function

点击翻译按钮获取中文摘要

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.