Naïve CD8+ T cell activation triggers their differentiation into cytotoxic T cells (CTLs) capable of eliciting immune control of virally infected cells and cancer. This control is mediated via acquisition of effector molecules such as granule enzymes (granzymes), perforin and pro-inflammatory cytokines. Upon immune control of the virus infection or cancer, the CTL effector response contracts leaving behind a small pool of long-lived memory cells which exhibit rapid effector function upon re-infection to provide T cell mediated immunity. While coordinated changes in gene transcription and differential chromatin accessibility underly CD8+ T cell differentiation and subsequent memory cell fate decisions, the molecular mechanisms are not fully elucidated.
The addition and removal of histone posttranslational modifications by specific chromatin binding protein complexes are known to epigenetically regulate gene transcription during CD8+ T cell differentiation and modulate cell fate determination. The Polycomb Repressive complex 1 (PRC1) has been identified as a key factor in determining cellular differentiation in embryonic stem cells via deposition of ubiquitination of lysine 119 of the histone H2A subunit (H2A119KUb). Importantly, the role of PRC1 and specifically H2AK119Ub in regulating CD8+ T cell differentiation is poorly understood. Here we demonstrate that core components of the PRC1 complex are dynamically regulated early after CD8+ T cell activation and bind to key transcriptional regulators required for CD8+ T cell differentiation. Mice with a T cell specific deletion of PRC1 components exhibited increased proliferative and polyfunctional capacity when challenged with influenza-A during primary immune responses. However, upon rechallenge with serologically distinct IAV strains, reactivated memory CTLs displayed hallmark characteristics of immunological exhaustion despite the acute nature of the infection. Therefore, PRC-1 appears to be required to limit terminal differentiation and preserve stemness of through silencing lineage-specific genomic loci in CTLs, and is thus indispensable for functional memory formation.