Polycomb repressive complex 2-mediated chromatin repression guides effector CD8+ T cell terminal differentiation and loss of multipotency

To understand immunological memory formation, it is essential to elucidate how multipotent memory precursor (MP) cells maintain plasticity and longevity to seed a diverse and protective memory T cell pool. Profiling active (H3K27Ac) and repressed (H3K27me3) chromatin in naïve, MP and terminally differentiated effector (TE) CD8+ T cells during viral infection demonstrated increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro–effector genes in MP cells, indicative of multipotency. PRC2-deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8+ memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, likely due to diminished FOXO1 transcription factor expression. These results outline a temporal model for how effector T cells lose memory cell potential through selective epigenetic-silencing of pro-memory genes.