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. 2021 Aug 26;12:725618. doi: 10.3389/fimmu.2021.725618

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Copyright © 2021 Gonzalez, Zou, Gu and Chen

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Transcriptional and epigenetic regulation of T cell stemness and exhaustion. Transcription factors TCF1, BACH2, Id3, and c-Myb promote memory T cell formation as well as stemness in T_PEX cells. TCF1, BACH2, and c-Myb also restrain effector T cell differentiation. c-Myb is a transcriptional activator of Tcf7. Under chronic antigen exposure or high antigen load, the TCR-NFAT-TOX/NR4A axis drives the exhaustion program of T cells and promotes the expression of multiple inhibitory receptors. TOX/TOX2 and NR4As are secondary transcription factors induced by initiating NFAT. Epigenetic mechanisms, such as histone modifications and DNA methylation, act in concert with transcription factors to regulate T cell states. SUV39H1 and EZH2 silence stem/memory genes during effector T cell differentiation by methylating H3K9 and H3K27, respectively. Dnmt3a mediates de novo DNA methylation to inhibit the expression of stem/memory genes during effector differentiation. T_EX cells have an epigenetic profile distinct from that of T_EFF and memory T cells, though how epigenetic enzymes regulate the expression of exhaustion genes remains unclear.