Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity

Abstract

Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8+ T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

“…NAD + is a regulator of Sirtuin1 (SIRT1), which has deacetylase activity (Aksoy et al, 2006) in T cells (Jeng et al, 2018), cancer cells (Chatterjee et al, 2018), and adipocytes (Cantó and Auwerx, 2012) because SIRT1 binds NAD + to deacetylate targets (Sauve et al, 2006). One of the molecules, which is deacetylated by SIRT1, is EZH2 (Wan et al, 2015), which modulates epigenetically the expression of several molecules including T-bet, RUNX3, and EOMES by trimethylating histone 3 at lysine 27 (H3K27me3) (Fujii et al, 2008;He et al, 2017;Tong et al, 2014). It has been reported that SIRT1 regulates the activity and stability of EZH2 by acetylating it at lysine 348 in HEK293T cells (Wan et al, 2015).…”

Integrative network modeling reveals mechanisms underlying T cell exhaustion

“…For example, transcription of EZH2 (the core subunit of PRC2) is up-regulated following TCR co-stimulation, peaks at ~1 day post-infection, and is largely back to basal levels by day 7 post-infection 30 . At the protein level, PRC2 activity peaks around 3-5 days postinfection 41,42 , at which time EZH2/PRC2 suppress the already active pro-memory/proliferation genes FOXO1 and TCF-1 while suppressing the pro-effector/exhaustion gene EOMES ( Fig. 7 and Fig.…”

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…T cell differentiation is intimately linked to epigenetic programming, but the mechanistic role of epigenetic marks in steering T cell differentiation 40,60,61,63,69,70 and thymic selection [71][72][73][74][75] has only recently become more clear. Here we observed that ablation of Dot1L in the T cell lineage differentially affected CD4 + and CD8 + T cells.…”

“…Sets of differentially expressed genes in indicated conditions were called 'gene signatures'. An exception was made for the Ezh2 RNA-Seq data from He et al, 61 wherein the dispersion was estimated with a local fit, using `estimateDispersion` function in DESeq2 with the argument `fitType = "local"` and using an adjusted pvalue cutoff of 0.05, to increase the number of detected differential genes. Principal component analysis was performed using the `prcomp` function on variance stabilizing transformed data of all samples with the `vst` function from the DESeq2 package on all samples using default arguments.…”

“…5d), and Dot1L-KO mice share several T-cell phenotypes with Ezh2-KO mice 40,60 , although this is dependent on the mouse model used [61][62][63] . To further investigate the idea that misregulation of PRC2 targets could be one of the downstream consequences of loss of DOT1L in CD8 + T cells, we compared the gene expression changes in an Ezh2-KO model 61 with those seen in Dot1L-KO CD8 + T cells. This revealed substantial overlap between the derepressed genes in the two models ( Fig.…”