Epigenetic Regulation of CD8+ Effector T Cell Differentiation by PDCD5

Abstract

Epigenetic modification plays a crucial role in establishing the transcriptional program that governs the differentiation of CD8⁺ effector T cells. However, the mechanisms by which this process is regulated at an early stage, prior to the expression of master transcription factors, are not yet fully understood. In this study, we have identified PDCD5 as an activation-induced molecule that is necessary for the proper differentiation and expansion of antigen-specific CD8⁺ effector T cells in a mouse model of chronic viral infection. The genetic deletion of Pdcd5 resulted in impaired differentiation and function of effector T cells, while T-cell activation, metabolic reprogramming, and the differentiation of memory/exhausted T cells were largely unaffected. At the molecular level, we observed reduced chromatin accessibility and transcriptional activity of Tbx21 and its regulated genes in Pdcd5^−/− CD8⁺ T cells. We further identified that PRDM9 facilitates the H3K4me3 modification of genes associated with the effector phenotype in CD8⁺ T cells. The interaction between PDCD5 and PRDM9 promotes the nuclear translocation and lysine methyltransferase activity of PRDM9. Collectively, these findings highlight the crucial role of the PDCD5/PRDM9 axis in epigenetic reprogramming during the early stages of fate determination for effector CD8⁺ T cell fate.