Figure 4:

TOX-related regulatory network in CD8⁺T cell exhaustion. The arrow represents a positive (stimulatory) connection. The solid line represents a link based on genetic evidence, mostly whether this linkage is through direct or indirect binding of transcription factors to target genes remains to be determined. Persistent antigens activated T-cell receptor (TCR) triggers calcineurin and NFAT signaling. NFAT is a core mechanistic driver of CD8⁺ T cell exhaustion. TOX, TOX2, and NR4A are targets of the NFAT and they are also key factors in the transcriptional program of CD8⁺ T cell exhaustion downstream of NFAT. There also exists a feed-forward loop between TOX and NR4A. Besides, TOX is necessarily and sufficiently induced by NFAT2 and participates in the feed-forward loop. In this loop, TOX becomes calcineurin-independent and maintained within this loop in all Tex cells. Of note, VEGF-A also induced the expression of TOX to drive the exhaustion-specific transcription program.