A network of bZIP transcription factors and inhibitors enforces differentially proliferative and cytotoxic states in T cells

A network of bZIP transcription factors and inhibitors influence T-cell proliferation and cytotoxicity, according to a recent study. The research reveals that varying bZIP TF activity through overexpression or inhibition impacts CAR T-cell expansion under conditions of exhaustion. This method employs inhibitors targeting pro-exhaustion TFs, like CREM and NFIL3, providing insight into the roles of full-length TFs.

BATF2 emerges as an underappreciated bZIP TF with anti-exhaustion potential. A series of tests on various bZIP TFs and inhibitors uncovers distinct effects on proliferation, persistence, and cytotoxicity. Pairings of pro-cytotoxic JUN, pro-proliferative BATF2, and the novel inhibitor AEL-CREM of pro-dysfunction CREM yield combinations that enhance either cytotoxicity or proliferation, indicating relationships between BATF2, JUN-, and CREB1-family bZIPs.

Further investigation reveals functional overlap in the inhibition of pro-dysfunction CREB1-family activity by BATF2 and AEL-CREM, possibly through unexpected interactions of CREB1-family members with overexpressed BATF2. BATF2's influence extends to early promotion of pro-proliferation AP-1 activity and later interactions with BACH2, contributing to persistence.

These discoveries are corroborated in murine chronic viral infection and syngeneic tumor models, where BATF2 or AEL-CREM overexpression demonstrates pro-proliferative and anti-exhaustion effects. The findings shed light on new connections and functional roles of bZIP family perturbations, offering potential strategies to modulate T-cell states.