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Downregulation of Ezh2 promotes the differentiation of short-lived effector CD8 T cells and weakens antitumor immunity

ABSTRACT: T-cell function is epigenetically regulated, however its precise role in tumor immunity is not fully understood. Ezh2 promotes transcriptional silencing through trimethylation of histone H3K27. We previously reported that the methylation level of histone H3K27 decreases in terminally differentiated and senescent T cells. In this study, we analyzed the role of Ezh2 in the differentiation of effector CD8⁺ T cells and antitumor immunity. In a mouse tumor model, T-cell-specific Ezh2 KO mice exhibited reduced initial tumor growth compared to wild-type (WT) mice, but tumors grew rapidly after day 7. The number of CD8⁺ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Ezh2 KO mice. We found that although the expression of effector molecules was rapidly increased in Ezh2 KO CD8⁺ T cells compared to WT cells, apoptotic cell death was also rapidly induced after activation. RNA-sequencing revealed that the expression of effector signature genes was upregulated in Ezh2 KO effector CD8⁺ T cells, along with the expression of apoptosis-related genes. These findings suggest that Downregulation of Ezh2 promotes the differentiation of short-lived effector CD8 T cells and weakens antitumor immunity. These findings suggest that downregulation of Ezh2 promotes the differentiation of short-lived effector CD8⁺ T cells and impairs sustained antitumor immunity. Maintaining appropriate levels of H3K27 trimethylation may be essential for the long-term persistence of effective antitumor T cell responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE305573 | GEO | 2026/07/29

REPOSITORIES: GEO

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Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.

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Downregulation of Ezh2 promotes the differentiation of short-lived effector CD8 T cells and weakens antitumor immunity

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