Abstract
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.
Highlights
During acute infection, antigen-specific CD8+ T cells are activated and differentiate into cytotoxic effector cells to clear pathogens
Recently identified long-lived effector (LLE) cells, which are distinguished by the highest level of CX3CR1 among T effector memory (TEM)-like cells have the most robust cytotoxic function when compared with other memory CD8+ T cells [3]
We observed that Clusters 0–2 expressed genes previously associated with TEM (Il7r, Cxcr3, intermediate levels of Cx3cr1 and Klrg1), T central memory (TCM) (Sell, Ccr7, Lef1, and Tcf7), and LLE (high levels of Cx3cr1, Klrg1, Tbx21, and Zeb2), respectively [3,19,20] (Figure 1D–F)
Summary
Antigen-specific CD8+ T cells are activated and differentiate into cytotoxic effector cells to clear pathogens. LLE cells share similar features with CX3CR1hi TEM and further studies may be needed to determine if these two populations are, identical In addition to these circulating memory subsets, tissue-resident memory (TRM) cells are found in various tissues, especially at barrier surfaces, such as the skin, lung, female reproductive tract, and intestinal epithelium [4,5]. Runx3 [15], Notch [16], Bhlhe40 [17], and Blimp and its homolog Hobit [18] are reported to regulate TRM formation, it remains unclear whether potentially heterogeneous subpopulations of TRM cells may be controlled by distinct TFs. Here, we applied single-cell RNA sequencing (scRNA-seq) on GP33+ CD8+ T cells from spleen and small intestine post LCMV-Armstrong (LCMV-ARM) infection to test the heterogeneity of circulating memory populations and TRM cells. Our study provides a framework to systematically identify critical regulators for each CD8+ memory T-cell population
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