ATAC-Seq of CD4+ T cell subsets during LCMV infection

Following an infection, CD4+ lymphocytes can differentiate into long-lived memory T cells, some of which circulate through the secondary lymphoid organs (SLOs) while a population lodges in non-lymphoid tissues. While CD4+ T cells in SLOs have been examined, the developmental origins and transcriptional regulation of tissue-resident memory T cells (TRM) remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profile of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by day 21 memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, we demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. Our results identify new significance for TFs previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation. 6 samples, 2 replicates each, Day 7 or Day 20 LCMV infection CD4+ T cell subsets