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

Abstract

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8 + T cells (TRM) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how TRM 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 hi TRM population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct TRM states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal TRM heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of shortlived and long-lived TRM-like subsets, which share qualities with terminally-exhausted and progenitorexhausted cells, respectively. As the clinical relevance of TRM 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.

Memory CD8+ T cell heterogeneity is primarily driven by pathogen-specific cues and additionally shaped by the tissue environment

“…In addition to T EM cell subsets and consistent with our data, heterogeneity within T RM cells exists (Kumar et al, 2017(Kumar et al, , 2018Milner et al, 2020). The latter is of interest, because these resident CD8 + T cells contribute significantly to local immunity (Gebhardt et al, 2009;Masopust et al, 2010;Steinert et al, 2015).…”

Tissue-resident memory T cells in gastrointestinal tumors: turning immune desert into immune oasis

“…Another single-cell sequencing results showed that Trm cells could be divided into three subsets: Hobitenriched CD103 hi PD-1 lo Trm, Granzyme K-enriched CD103 lo PD-1 hi Trm, and CD103 hi PD-1 hi CTLA hi LAG3 hi TIGIT hi Trm, while the last subset is considered as exhaustion-related subtype (79). Milne et al also identified subsets of memory T cells with resident gene expression characteristic of progenitor exhaustion T (Tpex) cell (Id3 hi Blimp1 lo ) and terminal exhaustion (80), and this study indicates that there exists a complete developmental pathway to exhaustion in Trm. In general, Trm cells may keep their function with the expression of immune checkpoints, but they still can convert into exhausted T cells.…”

Clone Wars: Survival of the Fittest CD8+ Trm Cells

“…First, what molecular mechanisms confer supe-rior fitness upon antigen-specific Trm cells, compared to bystander Trm cells, particularly in situations when active TGFb is limiting? Antigen-specific and bystander Trm cells exhibited similar transcriptomes, raising the possibility that epigenetic disparities or heterogeneity within these Trm cell populations, as has recently been observed (Kurd et al, 2020;Milner et al, 2020), might account for these differences. Second, precisely how TGFb controls the persistence of Trm cells remains incompletely understood.…”