TY - JOUR T1 - A unique epigenomic landscape defines CD8<sup>+</sup> tissue-resident memory T cells JF - bioRxiv DO - 10.1101/2022.05.04.490680 SP - 2022.05.04.490680 AU - Frank A. Buquicchio AU - Raissa Fonseca AU - Julia A. Belk AU - Maximilien Evrard AU - Andreas Obers AU - Yanyan Qi AU - Bence Daniel AU - Kathryn E. Yost AU - Ansuman T. Satpathy AU - Laura K. Mackay Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/06/2022.05.04.490680.abstract N2 - Memory T cells provide rapid and long-term protection against infection and tumors. The memory CD8+ T cell repertoire contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. While these T cell populations have been well characterized in terms of differentiation potential and function, the epigenetic changes underlying memory T cell fate determination and tissue-residency remain largely unexplored. Here, we examined the single-cell chromatin landscape of CD8+ T cells over the course of acute viral infection. We reveal an early bifurcation of memory precursors displaying distinct chromatin accessibility and define epigenetic trajectories that lead to a circulating (TCIRC) or tissue-resident memory T (TRM) cell fate. While TRM cells displayed a conserved epigenetic signature across organs, we demonstrate that these cells exhibit tissue-specific signatures and identify transcription factors that regulate TRM cell populations in a site-specific manner. Moreover, we demonstrate that TRM cells and exhausted T (TEX) cells are distinct epigenetic lineages that are distinguishable early in their differentiation. Together, these findings show that TRM cell development is accompanied by dynamic alterations in chromatin accessibility that direct a unique transcriptional program resulting in a tissue-adapted and functionally distinct T cell state.Graphical Abstract scATAC atlas reveals the epigenetic variance of memory CD8+ T cell subsets over the course of acute infectionEarly bifurcation of memory precursors leads to circulating versus tissue-resident cell fatesIntegrating transcriptional and epigenetic analyses identified organ-specific TRM cell regulators including HIC1 and BACH2Epigenetic distinction of TRM cells and TEX cell subsetsCompeting Interest StatementA.T.S. is a scientific founder of Immunai and founder of Cartography Biosciences and receives research funding from Merck Research Laboratories, 10x Genomics, and Allogene Therapeutics. ER -