Chromatin repression by PRC2 results in reduced gene expression driving key features of CD8 T cell exhaustion [Cut & Run]

Exhausted CD8 T cells result from chronic antigen stimulation and have reduced ability to clear disease. The epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing an in vitro model, we show global increase of the repressive histone modification H3K27me3 in CD8 T cell exhaustion as well as increased gene expression of the subunits of PRC2, the complex responsible for H3K27me3 deposition. H3K27me3 correlated with decreased gene expression and localized to naïve/memory T cell genes in CD8 T cell exhaustion. PRC2 inhibition increased expression of many of these naïve/memory genes while reducing expression of key exhaustion genes. Further, we identified potential enhancers and transcription factors predicted to promote expression of the PRC2 subunits. Our study highlights the importance of the repressive epigenetic landscape of exhausted CD8 T cells as well as a novel role for PRC2 in T cell biology. Overall design: CUT&RUN data for H3K27ac or H3K27me3, derived from acute or chronic exhausted CD8+ T cells; H3K27ac ACUTE 4 reps, H3K27ac CHRONIC 4 reps, H3K27me3 ACUTE 3 reps, H3K27me3 CHRONIC 3 reps