Early precursors and molecular determinants of tissue-resident memory CD8 ⁺ T lymphocytes revealed by single-cell RNA sequencing

Abstract

During an immune response to microbial infection, CD8+ T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we used single-cell RNA sequencing to examine the gene expression patterns of individual CD8+ T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional heterogeneity within the siIEL CD8+ T cell population at several stages of differentiation, representing functionally distinct TRM cell subsets and a subset of TRM cell precursors within the tissue early in infection. Together, these findings may inform strategies to optimize CD8+ T cell responses to protect against microbial infection and cancer.

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

“…Conversely, a small number of cells in acute LCMV infection had progressed to a differentiated effector memory state, and potentially also to dysfunctional state by day 7. These findings are consistent with previous smaller-scale scRNA-seq studies of functional or dysfunctional T cells across tissues (18,30,31,44,45) but reveal a more nuanced comparison of acute vs. chronic immune responses, where different trajectories are possible but occur with different frequencies.…”

“…This again confirmed the emergence of progenitor-like cells early in chronic infection, together with a small number of similar cells in acute infection, that clustered with dysfunctional progenitor cells, consistent with recent reports (20,54). We independently confirmed the presence of this CD8 T cell subpopulation at d7 in acute infection by reanalysis of three recently published scRNA-seq data sets (30,31,44) and confirmed enrichment of genes Tox, Ikzf2, Cxcr5 in this subpopulation (Supplementary Figure 13D). However, we also observed evidence of differential expression within the scRNA-seq cluster 9 between cells from different samples ( Supplementary Figure 14).…”

“…Thus, our analysis identified cell clusters encompassing archetypal CD8 T cell subsets including naïve T cells, memory precursor cells, short-lived effector cells, central memory, effector memory, terminally dysfunctional cells and their precursors. This cellular spectrum is similar to but more detailed than previously published scRNA-seq datasets of CD8 T cell responses in acute or chronic infection (18,30,31,44,45), suggesting that these cellular states are consistently generated across independent studies, and using mice of distinct genetic backgrounds.…”

“…C. MAGIC-imputed gene expression in individual samples. D. Enrichment of progenitor markers in a cluster of cells profiled at d7 in acute LCMV infection in three studies(30,31,44). Shown are significant (q < 0.01) log2 fold change values of expression in a selected cluster as compared with cells from all other clusters, as identified by diffxpy.…”

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

“…Ahr-deficient mice have dysfunctional skin and intestinal gdT cells and absent IEL (172,174), with reduced capacity for T H 17 differentiation and IL-22 secretion. AhR expression in CD8 + T cells is crucial for T RM and IEL persistence in tissues (175,176), while cytokines upregulate AhR expression in NK cells and iNKT to promote cytotoxicity and IL-22 production respectively (66,177).…”