Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation

The memory CD8(+) T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8(+) T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (T-RM) cells and circulating memory T (T-CIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of T-RM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to T-RM cells across organs. Finally, we found that although terminal T-EX cells share accessible regulatory elements with T-RM cells, they are defined by T-EX-specific epigenetic features absent from T-RM cells. Together, this comprehensive data resource shows that T-RM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.