Epigenetic regulation of CD8+ effector T cell differentiation by PDCD5

Epigenetic modification is critical in the establishment of the transcriptional program for CD8+ effector T cell differentiation. How this is regulated at an early stage before the expression of master transcription factors remains elusive. Here, we identify PDCD5 as an activation-induced molecule that is required for proper differentiation and expansion of antigen-specific CD8+ effector T cells in a chronic viral infection mouse model. Genetic deletion of Pdcd5 diminished effector T cell formation and function, leaving T cell activation, metabolic reprogramming, and memory/exhausted T cell differentiation largely unaffected. At the molecular level, reduced chromatin accessibility and transcription of Tbx21 and its regulated genes were found in Pdcd5-/- CD8+ T cells. We further identify PRDM9 that facilitates the H3K4me3 modification of effector signature genes in CD8+ T cells. The interaction of PDCD5 with PRDM9 promoted the translocation and lysine methyltransferase activity of PRDM9. These data indicate a pivotal role of PDCD5/PRDM9 axis in epigenetic reprogramming at the early stage of effector CD8+ T cell fate determination.