Fig. 3: Transcriptional regulatory network of exhausted CD8⁺ T cells.

T cell receptor (TCR) activation triggers phosphorylation of the kinase Lck, which in turn activates calcineurin pathways. Calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), which then translocates into the nucleus and regulates genes involved in either T cell effector function or T cell exhaustion. Therefore, the transduction of extracellular signals by NFAT is one of the most important steps in T cell exhaustion. On the one hand, NFAT represses TCF1 in exhausted CD8⁺ T cells since TCF1 can induce the formation of terminal effector and memory CD8⁺ T cells by upregulating EOMES expression. On the other hand, NFAT induces the transcription factors TOX and NR4A, which execute the exhaustion program of CD8⁺ T cells. It should be noted that TCF1 is necessary in the progenitors of exhausted T cells, but it should be repressed in terminally differentiated exhausted T cells.