HDAC3 is required for thymocyte positive selection (HEM2P.236)

Abstract

Abstract In order to generate functional peripheral T cells, proper gene regulation during T cell development is critical. Development involves both the activation and repression of genes as cells progress through each developmental checkpoint. Histone acetylation/deacetylation is one mechanism regulating gene expression. Acetylation by histone acetyl transferases (HATs) allows for gene expression and deacetylation by histone deacetylase (HDAC) enzymes promote gene silencing, and their role in regulating T cell development is not clear. In this study, our lab focused on HDAC3. We examined the role HDAC3 plays during T cell development by utilizing a CD2-Cre-mediated loss of HDAC3 (CD2icre HDAC3-cKO), which deletes early in thymocyte development. When HDAC3 is absent, there is a developmental block during positive selection, leading to the production of very few CD4 and CD8 SP thymocytes leading to a severe defect in peripheral T cell numbers. During positive selection, HDAC3-deficient DP thymocytes fail to down-regulate RORγt as they progress to the SP stage. Consistent with the failure to down-regulate RORγt, thymocytes post-positive selection express high levels of Bcl-xl and fail to express Bcl-2, which is required for their survival. Moreover, HDAC3-deficient thymocytes show increased apoptosis. These results suggest that HDAC3 is required for the down-regulation of RORγt during positive selection.