Ezh2 Inhibits the Differentiation of Short‐Lived Effector CD8 + T Cells and Promotes T Cell‐Dependent Antitumor Immunity
Open Access
- 2 June 2026
- journal article
- Published by Wiley in Cancer Science
- Vol. 117 (10) , 2644-2658
Abstract
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.Keywords
Funding Information
- Naito Foundation
- Takeda Medical Research Foundation
- Japan Society for the Promotion of Science (23K27427)
- Japan Society for the Promotion of Science (24K11367)
- Japan Society for the Promotion of Science (24K18470)
- Japan Society for the Promotion of Science (25K10214)
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