Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8(+) T cells underlies distinct functional potential.

Persistent antigen stimulation promotes differentiation of exhausted CD8(+) T (T(EX)) cells. T(EX) cells are distinct from circulating memory T (T(CIRCM)) cells but share many features with tissue-resident memory (T(RM)) cells established following infection resolution. CD8(+) T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional T(RM) or T(EX) cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident T(EX) (TR-T(EX)) cells that are ontologically and functionally distinct from T(RM) cells generated after antigen clearance. TR-T(EX) phenotypically resembled T(RM) cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although T(EX) progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional T(RM) cells after antigen withdrawal. Conversely, T(RM) cells were able to differentiate into T(EX) cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-T(EX) cells with patient responses to immune checkpoint blockade, and only TR-T(EX) but not T(RM) cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T(EX) and T(RM) cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.