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.
Highlights
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
To evaluate the impact of Ezh[2] in CD8+ T-cell responses, we used an experimental adoptive cell therapy (ACT) model, of which transferred T cells were more effective in controlling tumor growth in lymphopenic mice compared with lymphoreplete hosts[4,11,28]
Using lymphopenic recipients without B16 tumor, we observed that the frequency and number of WT and Ezh2−/− Pmel-1 cells was similar in the spleen 4 days after transfer and immunization, while Ezh2−/− Pmel-1 cell numbers were decreased by 7 days and days (Fig. 1b)
Summary
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. We show that the histone methyltransferase Ezh[2] controls CD8+ T memory precursor formation and antitumor activity. Ezh[2] activates Id3 while silencing Id2, Prdm[1] and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh[2] and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Major transcription factors (TFs), including Id3, Id2, T-bet, Eomes and Blimp-1 control the differentiation and function of effector and memory cells[1,3]. The mechanism by which CD8+ T cells epigenetically integrate Akt signaling and these major TFs to regulate the memory potential for controlling tumor growth remains poorly defined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
