HDAC3 is required to suppress the CD8-lineage program in DP thymocytes for CD4-lineage T cell commitment

Abstract

Abstract MHC-restricted CD4 and CD8 T cells are vital components of the immune system. The decision to generate CD4 or CD8 T cells occurs in the thymus. After positive selection, intermediate thymocytes downregulate CD8 to test coreceptor specificity. Thymocytes develop into CD4 T cells if they experience persistent TCR signaling, while termination of TCR signaling leads to IL-7-mediated CD8-lineage commitment via Runx3. While the general signaling and transcriptional mechanisms are known, the epigenetic mechanisms controlling error-free lineage commitment are largely unknown. We found histone deacetylase 3 (HDAC3) to be critical for generating CD4 T cells, as its deletion leads to the generation of only CD8SP cells. Introduction of an OT-II TCR transgene revealed redirection of MHC class II-restricted cells to the CD8 lineage upon HDAC3 deletion. We found evidence that HDAC3-deficient DP thymocytes are primed for the CD8-lineage, as they exhibit hyperacetylation at CD8-lineage promoting genes and show elevated expression of phosphorylated-STAT5 (pSTAT5). During lineage choice, OT-II expressing HDAC3-deficient cells inappropriately upregulate Runx3. Therefore, HDAC3 functions as a brake in DP thymocytes whose release leads to a developmental bias for CD8 T cells.