Id2 epigenetically controls CD8⁺ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

CD8⁺ T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6⁺ progenitor exhausted (Tex^prog) and Tim-3⁺ terminally exhausted (Tex^term) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8⁺ T-cell immunity. However, the role of Id2 in CD8⁺ T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Tex^prog cells and their conversion to Tex^term cells. Genetic deletion of Id2 dampens CD8⁺ T-cell-mediated immune responses and the maintenance of stem-like CD8⁺ T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6⁺ Tex^prog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6⁺Tim-3^- Tex^prog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8⁺ T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8⁺ T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.