The transcription factor BATF pioneers the differentiation program of cytolytic effector CD8+ T cells through the direct interaction with IRF4

Abstract

The transcription factor BATF plays critical roles in the differentiation of various immune cells, including CD8+ T cells. Here, we demonstrated that BATF controls epigenomic and transcriptomic reprogramming of CD8+ T cells at an early phase of acute viral infection, thereby promoting the differentiation of cytolytic effector CD8+ T cells. Loss of BATF drastically perturbed gene expression, chromatin accessibility, and the bindings of key transcription factors including Jun, T-bet, and IRF4. The direct interaction with IRF4 was essential for BATF-mediated effector differentiation, as the BATF mutant lacking this interaction failed to induce proper chromatin remodeling and proliferation of antigen-specific CD8+ T cells. Notably, IRF4 binding was exhaustively dependent on BATF, whereas BATF retained binding capacity even in IRF4-deficient CD8+ T cells. Furthermore, BATF initiated chromatin remodeling in the absence of IRF4, whereas subsequent dynamic epigenomic reorganization required IRF4. Our data proposed that BATF serves as a "pioneer transcription factor" spearheading the reorganization of chromatin architecture upon antigen encounter, followed by further rearrangement of epigenomic and transcriptomic landscapes through the cooperation with IRF4.