Ezh2 Inhibits the Differentiation of Short-Lived Effector CD8+ T Cells and Promotes T Cell-Dependent Antitumor Immunity.

Appropriate regulation of the differentiation balance between effector CD8+ T cells and memory CD8+ T cells is crucial for an appropriate immune response. We previously reported that the tumor suppressor menin suppresses the differentiation of CD8+ T cells into short-lived effector T cells (SLECs) and positively regulates memory CD8+ T cell differentiation. In this study, we identified Ezh2, a histone H3K27 methyltransferase, as a factor responsible for regulating SLECs differentiation, located downstream of menin. In antigen-stimulated CD8+ T cells, the Ezh2 expression gradually decreased with proliferation, reaching the lowest levels in terminally differentiated CD8+ T cells. The decrease in the expression of Ezh2 was accelerated by menin deficiency. Reduced histone H3K27 acetylation at the Ezh2 locus was observed in Menin-deficient CD8+ T cells, indicating that menin is required for maintaining the expression of Ezh2. In vitro studies have demonstrated that Ezh2-deficient activated CD8+ T cells exhibit enhanced differentiation into SLECs, along with increased effector functions. In contrast, Ezh2-deficient effector CD8+ T cells showed a marked increase in apoptosis upon IL-2 removal. In studies using mouse tumor models, T cell-specific Ezh2 knockout mice exhibited increased tumor growth and reduced survival relative to wild-type mice, with a significant decrease in the number of tumor-infiltrating CD8+ T cells. RNA sequencing revealed that Ezh2-deficient effector CD8+ T cells exhibit the increased expression of terminal differentiation-related molecules and apoptosis-related genes. These results demonstrate that Ezh2 functions downstream of menin and is essential for the proper regulation of T cell-dependent antitumor immunity.