Divergent ontogeny of tissue resident memory and tissue resident exhausted CD8 T cells underlies distinct functional potential 4588

Abstract Description Cancer and chronic infections drive the development of exhausted CD8 T cells (TEX). Although TEX are distinct from conventional circulating memory T cells (TMEM), they share several features with tissue-resident memory cells (TRM) that develop after acute infection. CD8 T cells co-expressing markers of terminal exhaustion and tissue-residency are abundant in tumors, where they frequently correlate with favorable immunotherapy responses. These cells are often classified as TRM because they express residency molecules like CD103, but whether they possess memory properties is unclear. Here we show that persistent antigen stimulation in nonlymphoid tissues during chronic infection induces a population of tissue-resident TEX (TR-TEX) cells that are developmentally and functionally distinct from TRM generated after infection resolution. TR-TEX and TRM were governed by distinct transcriptional and epigenetic circuitry, indicating divergent differentiation paths. Indeed, whereas TRM could give rise to antigen-independent TMEM as well as multiple TEX subsets after reinfection, TEX progenitors required ongoing antigen stimulation and the transcription factor Tox for residency programming. TRM and TR-TEX differentially associated with cancer patient survival, and TR-TEX but not TRM responded to PD1 checkpoint inhibition. Thus, TR-TEX and TRM are divergent cellular lineages that acquire a shared residency program but play distinct roles in disease control and immunotherapy responses. Funding Sources S.L.P. was supported by a Cancer Research Institute Irvington Postdoctoral Fellowship. This work was supported by grants from the NIH, AI155577; AI115712; AI117950; AI108545; AI082630 and CA210944 (to E.J.W.) Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)