The transcription factors ETS1 and RUNX3 differentially specify effector memory and tissue resident memory CD8 T cell formation 3487

Abstract Description Activated CD8 T cells differentiate into effector memory (TEM) cells that recirculate in the vasculature and tissue resident memory (TRM) cells that do not, but the early transcriptional control that drives their specification is unclear. Here, we provide evidence that transcription factors (TFs) ETS1 and RUNX3 have distinct functions that polarize formation of TEM and TRM cells. Ets1-deficient effector (TEFF) cells inefficiently formed TEM cells, redistributed into the small intestine (SI) epithelium, exhibited increased TGFβ responsiveness and more strongly differentiated into CD69hi CD103hi cells, whereas Runx3-deficiency caused the alternative phenotype. ETS1 promoted chromatin accessibility of cis-regulatory regions encoding ETS and composite ETS:RUNX motifs, distinct from those that required RUNX3, and activated expression of both TEM cell genes and the TGFβ-inhibitory factor encoded by Smad7. Enforced Smad7 expression restored wildtype TGFβ responsiveness and CD103 expression in Ets1-deficient cells. Thus, ETS1 activates TEM cell development and represses TRM cell formation, whereas RUNX3 promotes TRM cell formation. Funding Sources Supported by P01AI145815; U01AI163063; and Frenchman Creek’s Women for Scripps Research. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)