ROLE OF CBX4 ON CD8 T CELL DIFFERENTIATION AND EFFECTOR FUNCTION

Cytotoxic CD8 T lymphocytes (CTLs) are key players in the elimination of intracellular pathogens and tumors. During acute infection, CTLs differentiate into a heterogeneous population composed of terminal effector and memory precursor cells (Nat. Rev. Immunol. (2012) 12:749). We have previously demonstrated the novel role of the epigenetic modulator Chromobox (Cbx) 4 in controlling CTL differentiation. Cbx4 is a member of the Polycomb Repressive Complex 1 (PRC1), responsible for ubiquitinating lysine 119 of histone H2A (H2AK119ub) via the catalytic subunit Ring1A/B, leading to gene expression repression. Cbx4 can recognize trimethylation at lysine 27 of histone H3 (H3K27me3), recruiting PRC1 to these sites (Cell (2007) 128:735). Here, we infected C57BL/6 Cbx4 fl/fl Cd4-Cre (Cbx4 TKO) mice, deficient in Cbx4 in the T-cell compartment, with the acute LCMV strain Armstrong 5 (CEUA/UFRJ 003/23) and observed an increased frequency of virus-specific memory cells with a precursor phenotype, which is desirable in immunotherapeutics, suggesting that Cbx4 regulates CTL stemness in acute settings. Even though we have previously shown that the effector function of Cbx4 T KO is compromised in vitro, we did not observe changes in serum LCMV titers during acute infection of Cbx4 TKO mice 7 days post-infection. Moreover, our preliminary data showed that Cbx4 TKO mice display superior tumor protection in a murine model of melanoma B16 (CEUA/UFRJ 041/20) with an increased presence of central memory cells. Taken together, our results suggest that even though Cbx4 deletion can reduce effector functions, it does not compromise acute viral clearance. Additionally, the deletion of Cbx4 induces a T cell progenitor capacity with potential to improve long term tumor control in immunotherapy strategies.