The transcription factor BATF pioneers the differentiation program of cytolytic effector CD8+ T cells through the direct interaction with IRF4 (CUT&RUN)
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. Overall design: This submission contains the CUT&RUN portion of the data. There are three datasets described below. (1) Wild-type and Batf-deficient P14 cells were FACS-sorted at days 0 and 3 post-infection with LCMV Armstrong. The bindings of BATF, IRF4, T-bet, JunB, JunD, and FoxO1 were analyzed. (2) CD4cre and IRF4-conditional knockout P14 cells were FACS-sorted at day 3 post-infection with LCMV Armstrong. The bindings of BATF were analyzed. (3) Batf-deficient P14 cells retrovirally transduced with Batf or Batf mutants were cultured in vitro. RV+ cells were FACS-sorted 3 days after RV transduction and the bindings of BATF and IRF4 were examined.