HDAC3 restrains cytokine signaling during thymocyte development for the generation of CD4 T cells (ChIP-Seq)

CD4 and CD8 T cells are vital components of the immune system. According to the kinetic signaling model, commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. We found histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as its deletion leads to the generation of only CD8SP thymocytes.  In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage.  Analysis of histone acetylation and RNA-seq reveals HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection.  In addition, HDAC3-deficient DP thymocytes have increased IL-21R expression and STAT5 activation.  As a result, HDAC3 is required to restrain cytokine signaling in DP thymocytes and is required for the generation of CD4 T cells. We used mRNA-seq to identify changes in gene expression and ChIP-seq to map epigenetic marks in DP thymocytes and TCR-int/CD69-positive thymocytes.