Single-Cell Transcriptomics Reveals Core Regulatory Programs That Determine the Heterogeneity of Circulating and Tissue-Resident Memory CD8+ T Cells

During acute infections, CD8(+) T cells form various memory subpopulations to provide long-lasting protection against reinfection. T central memory (TCM), T effector memory (TEM), and long-lived effector (LLE) cells are circulating memory populations with distinct plasticity, migration patterns, and effector functions. Tissue-resident memory (TRM) cells permanently reside in the frontline sites of pathogen entry and provide tissue-specific protection upon reinfection. Here, using single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq, we examined the different and shared transcriptomes and regulators of TRM cells with other circulating memory populations. Furthermore, we identified heterogeneity within the TRM pool from small intestine and novel transcriptional regulators that may control the phenotypic and functional heterogeneity of TRM cells during acute infection. Our findings provide a resource for future studies to identify novel pathways for enhancing vaccination and immunotherapeutic approaches.

Automated summary

During acute infections, different memory subpopulations of CD8(+) T cells provide long-lasting protection, with tissue-resident memory (TRM) cells offering tissue-specific protection. Heterogeneity within the TRM pool in the small intestine was identified, along with potential transcriptional regulators controlling TRM cell phenotype and function during acute infection. These findings contribute to identifying new pathways for enhancing vaccination and immunotherapeutic approaches in future studies.