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. 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.