Corepressors in CD4+ T cell development and homeostasis

Abstract

Abstract Corepressors NCOR1 and NCOR2/SMRT serve as scaffolds for the recruitment of histone deacetylases to transcription factor-DNA complexes. These closely related proteins are functionally non-redundant. Though they were first identified by their interactions with nuclear receptors, NCOR1/2 also interact with non-nuclear receptor transcription factors, including several involved in T cell development and polarization. Previous research identified that NCOR1 promotes survival of double positive thymocytes and protects them from negative selection. We have built upon this work by examining the effect of combined NCOR1/2 deletion in developing thymocytes. NCOR1/2 deletion using a CD4-Cre model results in an 8-fold decrease in the frequency of CD4 single positive T cells, compared to a 2-fold decrease and an insignificant decrease for NCOR1 and NCOR2 deletion alone, respectively. NCOR1/2-deficient T cells demonstrate exquisite sensitivity to TCR stimulation and polarize to Th subsets at different frequencies compared to wild-type CD4+ T cells. Despite a profound loss of CD4 single positive T cells and thymic regulatory T cells (Tregs), the frequency of both Treg progenitor populations remains unchanged. In contrast, the frequency of splenic Tregs is not reduced in NCOR1/2-deficient mice. However, there is a striking increase in activation of conventional T cells, suggesting that T cell tolerance is perturbed. Using an OX40-Cre deletion model which deletes NCOR1/2 in dendritic cells (DCs), activated T cells, and Tregs, we observe a decreased CD4+/CD8+ ratio and high incidence of ulcerative dermatitis. We are currently examining how Treg or DC specific deletion of NCOR1/2 affects T cell development, homeostasis, and tolerance.