Histone deacetylase 3 is necessary for T cell maturation (HEM2P.238)

Abstract

Abstract Recent thymic emigrants (RTEs) are newly generated T cells that need to undergo post-thymic maturation in the periphery. The mechanism of T cell maturation remains unclear. Histone deacetylase 3 (HDAC3) controls gene regulation, chromatin accessibility and genomic stability. However, the function of HDAC3 in T cell has yet to be elucidated. As we previously demonstrated that HDAC3 is a binding partner to NKAP, we hypothesize that HDAC3, like NKAP, may regulate T cell maturation. We generated CD4-cre HDAC3 cKO mice, which have similar numbers of DN, DP, CD4 SP and CD8 SP thymocytes as compared to WT mice; however, the peripheral numbers of CD4+ and CD8+ T cells are dramatically decreased in CD4-cre HDAC3 cKO mice. When we examined Rag1-GFP CD4-cre HDAC3 cKO mice, the majority of peripheral naïve T cells are Rag1-GFP+ RTEs indicating a block in T cell maturation. There is no defect in the positive selection, negative selection, migration, or homeostasis in CD4-cre HDAC3 cKO mice. However, expression of the complement inhibitor CD55, which is induced during maturation, is severely decreased. In the periphery, similar to NKAP-deficient T cells, HDAC3-deficient T cells are targeted for elimination by complement. In addition, HDAC3-deficient T cells have decreased sialic acid modifications on the cell surface, mainly due to α2-3, and α2-8 linkages, that recruit natural IgM to initiate the classical complement pathway. Thus, HDAC3 is required for T cell maturation.