Heterogenous Populations of Tissue-Resident CD8+ T Cells Are Generated in Response to Infection and Malignancy

Tissue-resident memory CD8+ T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we identified discrete lineages of intestinal antigen-specific CD8+ T cells, including a Blimp1hiId3lo tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1loId3hi tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8+ T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches. [Display omitted] •Blimp1 and Id3 expression identify distinct tissue-resident T cell subsets•Id3hi siIEL CD8+ T cells exhibit heightened multifunctionality and memory potential•Id2 and Id3 are required for homeostasis of tissue-resident memory cells•Id3hi cells in tumors have features of tissue-residency and progenitor exhausted cells Tissue-resident memory CD8+ T cells (Trm) provide long-lasting immunity in non-lymphoid tissues. Milner et al. use single-cell RNA sequencing to reveal Trm cell heterogeneity in response to infection and identify effector-like Id3loBlimp1hi and memory-like Id3hiBlimp1lo tissue-resident populations with differential effector function, memory potential, and transcriptional programming. Analogous populations of CD8+ T cells with tissue-residency features were also identified in tumors.