Highlights of IMMUNOLOGY2026™ - Invited Program Recordings-Early chromatin and transcriptional changes driven by NFAT and its transcriptional partners in 'exhausted' CD8+ T cells

Early chromatin and transcriptional changes driven by NFAT and its transcriptional partners in 'exhausted' CD8+ T cells

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Video Summary

The talk focused on how CD8 T cells become exhausted in tumors, especially melanoma, and the chromatin and transcriptional changes that drive this state. Early tumor-infiltrating T cells already show exhaustion-like features, including reduced TNF and IL-2 production, altered IFN-γ output, and early PD-1 expression. By day 3, gene expression patterns show both exhaustion-associated factors like NR4A and TOX and effector genes such as IFN-γ, granzyme B, and perforin.<br /><br />A major finding was that NFAT, activated by calcium/calcineurin signaling, rapidly opens chromatin genome-wide and at the TOX locus, helping initiate the exhaustion program. This opening is blocked by cyclosporine or loss of NFAT proteins. The chromatin changes are early and reversible, suggesting cells are still plastic at first.<br /><br />The team then identified transcriptional partners that cooperate with NFAT. Using TurboID mass spectrometry, they found several candidates, especially FOSL2. FOSL2 is expressed in tumor T cells and enhances NFAT-driven expression of exhaustion genes like HAVCR2 (TIM-3), NR4A3, and RGS16. Overall, the work suggests exhaustion is not a single program but a set of pathways, offering potential therapeutic targets upstream of NFAT.

Keywords

CD8 T cells

T cell exhaustion

melanoma

chromatin remodeling

NFAT signaling

TOX

FOSL2