BATF controls T cell differentiation during chronic antigen stimulation

Abstract

Abstract CD4+ T cells preserve self-tolerance in the periphery by exerting active suppression as regulatory T cells (Treg) or entering an inactive state known as anergy. Recent evidence suggests that anergy occurs naturally within a subpopulation of polyclonal CD4+ T cells and can generate precursors to Foxp3-expressing Treg cells. To identify transcription factors (TFs) underlying T cell anergy induction and its potential plasticity, we sorted polyclonal CD4+ T cell subsets from mice for downstream sequencing-based interrogation. Anergic CD44high Foxp3− CD73highFR4high Nrp1+ T cells were compared to effector-memory, Treg, and naïve T cell populations. Integrated ATAC-seq and RNA-seq analysis revealed a distinct program in the anergic T cell subpopulation. The anergy signature was driven by bZIP/AP-1 subfamily (Batf, Maf) and NFAT family (Nfatc1) transcription factors. Anergy-enriched TFs were then investigated in antigen-specific T cell tolerization systems where Batf knockdown led to altered expansion and minimal Treg cell differentiation. BATF was furthermore required for anergy-derived Foxp3+ Treg cell generation. Our data indicate that BATF orchestrates the transition to chronically-stimulated T cell differentiation states. Supported by grants from the NIH (T32 AI007313, P01 AI035296) and RRF (Future Physician Scientist Award)