BATF3 regulates differentiation of CD8+ T lymphocytes and memory differentiation program.

Abstract

CD8⁺ T lymphocytes differentiate from effector to memory cells after antigen clearance, with prolonged IL-2 production characterizing functional cytotoxic T lymphocytes (CTLs). To identify transcription factors associated with sustained IL-2 production, we compared influenza virus-specific and cytomegalovirus-specific CTLs, identifying Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3) as a key candidate. BATF3 overexpression significantly enhanced cell proliferation in both virus-specific CTLs and CD19 chimeric antigen receptor T (CAR-T) cells while reducing cytokine production. Among AP-1 transcription factor family members, BATF and BATF3 demonstrated similar functions during effector phase expansion, but BATF3 exhibited distinct roles in promoting memory cell formation. ATAC-seq analysis revealed that BATF3 overexpression dynamically regulates chromatin accessibility, affecting diverse cellular processes including cytoskeletal organization, metabolic pathways, and survival signaling. BATF and BATF3 showed comparable kinetics until peak expansion, but BATF3 specifically facilitated the transition from effector to memory phase, up-regulating memory-associated genes while down-regulating exhaustion markers. These findings establish BATF3 as a master regulator of CD8⁺ T-cell fate determination through chromatin remodeling, offering therapeutic targets for enhancing CAR-T cell persistence in immunotherapy.