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

Overexpressing bZIP TFs and protein-based inhibitors in CAR T cells under exhausting conditions shows BATF2 and AEL-CREM are notably pro-proliferative and anti-exhaustion in murine models.

• Why it matters: bZIP TF dimer networks make it hard to assign roles of individual members in T-cell exhaustion, and knockout or overexpression alone cannot resolve how activity shifts alter proliferative versus cytotoxic states.
• What they did: The authors screened full-length bZIP TF overexpression with genetically encoded inhibitors, then compared effects on proliferation, persistence, and cytotoxicity, including JUN, BATF2, and AEL-CREM targeting CREM.
• The result: Multi-omics and AP-MS mapping of BATF2 and AEL-CREM revealed functional overlap in suppressing pro-dysfunction CREB1-family activity, with BATF2 also promoting early pro-proliferation AP-1 and later interacting with BACH2 to support persistence.

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