Deciphering the role of histone modifications in memory and exhausted CD8 T cells

Exhausted CD8 T cells (TEX) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (TMEM) cells, TEX have a unique open chromatin landscape underlying a distinct gene expression program. How TEX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (TN), TMEM and TEX. We identified H3K27ac-associated super-enhancers that distinguish TN, TMEM and TEX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in TN, but activated in TMEM or TEX whereas other genes poised in TN were repressed in TMEM or TEX, indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in TEX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of TEX compared to TMEM through both activating and repressive pathways.