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. [Display omitted] • Memory T cell subsets develop along distinct epigenetic trajectories • T RM cells exhibit a distinct chromatin landscape from that of T CIRC cell subsets • Epigenetic analyses reveal novel organ-specific regulators of T RM cell development • T RM and T EX are epigenetically distinct but exhibit cis -regulatory element overlap Epigenomic features steering CD8+ T cell heterogeneity across tissues has not yet been extensively explored. By profiling chromatin accessibility changes and gene expression in T cells derived from multiple organs, Buquicchio et al. reveal the epigenetic state of memory CD8+ T cells and identify subset and organ-specific regulators involved in T cell differentiation. [ABSTRACT FROM AUTHOR]