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

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 (T_RM) 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 T_RM cell subsets and a subset of T_RM 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.