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. 2022 Jul 6;30(1):1–10. doi: 10.1038/s41417-022-00495-w

Fig. 3. The complex regulatory network of Tex.

Fig. 3

The chronic TCR signal is the core driver of exhaustion, which activates NFAT and its downstream molecules (for example, TOX, NR4A and IRF4) through calcineurin, thereby up-regulating the expression of inhibitory receptors and maintaining the survival of T cells. In the absence of transcription factor AP-1, NFAT activates negative regulatory programs in CD8+ T cells and induces low reactivity in T cells. Then, activation of the secondary transcription factors TOX and NR4A will initiate the CD8+ Tex transcription process. TOX promotes and maintains Tex, while NR4A induces PD-1 and TIM-3 expression and weakens the anti-tumor effect of T cells. BATF is a downstream molecule of PD-1, which can inbibit T cells proliferation, cytokine secretion, and TOX when it combines with IRF4. In addition, transcription factor TCF1 is helpful for maintaining the stem cell-like characteristics of TILs and inducing the transformation of progenitor exhausted T cells. The PI3K/AKT/FOXO1 signaling network is activated by costimulatory molecule CD28. FOXO1 promotes the expression of TCF1, which mediates the transformation of T-bet-to-Eomes transcription factors by promoting Eomes expression in progenitor exhausted CD8+ T cells. TCF1 can also promote the expression of BCL-6 and c-Myb. The latter controls the survival and expression of BCL-2. The overexpression of Eomes induces Tex by activating B7S1. It is worth noting that Blimp-1, like T-bet, can also promote Tex, but Blimp-1 is inhibited by TCF-1. In addition, IRF9 may inhibit the exhaustion of TILs. As for metabolism, mTOR regulates the metabolic checkpoint of glycolysis through transcription factors HIF-1α and c-Myc and participates in methylation-specific exhausted procedures through epigenetic enzymes such as DNMT3A. Moreover, the de novo DNA methyltransferase DNMT3A induces epigenetic silencing of effector and memory-related genes by de novo DNA methylation.