Functional delineation of tissue-resident CD8 + T cell heterogeneity during infection and cancer

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8 T cells (T) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how T confer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8 T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3 T population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct T states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal T heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of short-lived and long-lived T-like subsets, which share qualities with terminally-exhausted and progenitor-exhausted cells, respectively. As the clinical relevance of T continues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8 T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.