Using scRNASeq, Milner et al. identified unique transcriptional signatures and regulators associated with tissue-resident memory (Trm) CD8+ T cells from the small intestine compared to circulating memory T cells in lymphoid organs. Like circulating T cells, Trms were heterogeneous, and over the course of viral infection transitioned from a Blimp1hiKLRG1hi effector phenotype to an Id3hiCD127hi stem-like signature. These populations were transcriptionally and functionally distinct, and were detected in multiple tissues including tumors, where Blimp1 denoted a terminally exhausted CD8+ T cell population while Id3 linked with stemness and progenitor exhaustion.
Contributed by Alex Najibi
ABSTRACT: 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 Blimp1(hi)Id3(lo) tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1(lo)Id3(hi) 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.