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

Exhausted CD8 T cells (T_EX) 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 (T_MEM) cells, T_EX have a unique open chromatin landscape underlying a distinct gene expression program. How T_EX 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 (T_N), T_MEM and T_EX. We identified H3K27ac-associated super-enhancers that distinguish T_N, T_MEM and T_EX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in T_N, but activated in T_MEM or T_EX whereas other genes poised in T_N were repressed in T_MEM or T_EX, 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 T_EX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of T_EX compared to T_MEM through both activating and repressive pathways.