Abstract
Background: Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8 + T-cell responses, described as memory "inflation". These retain functionality, home to peripheral organs and are associated with a distinct transcriptional program. Methods: To further define the nature of the transcriptional mechanisms underpinning memory inflation at different sites we used single-cell RNA sequencing of tetramer-sorted cells from MCMV-infected mice, analyzing transcriptional networks in virus-specific populations in the spleen and gut intra-epithelial lymphocytes (IEL). Results: We provide a transcriptional map of T-cell memory and define a module of gene expression, which distinguishes memory inflation in spleen from resident memory T-cells (T RM) in the gut. Conclusions: These data indicate that CD8 + T-cell memory in the gut epithelium induced by persistent viruses and vaccines has a distinct quality from both conventional memory and "inflationary" memory which may be relevant to protection against mucosal infections.
Highlights
Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”[1]
Following intravenous (i.v.) infection of C57BL/6 mice with 106 plaque-forming units Murine CMV (MCMV), two distinct memory responses – a conventional contracting response (M45-tetramer+) and an inflating response (M38-tetramer+) - were detected in spleen and intra-epithelial lymphocytes (IEL) (Figure 1A-B) [2,3]
To explore the transcriptional mechanisms governing memory inflation in different tissues, we performed single-cell RNA sequencing of M38-tetramer+ CD8+ T-cells from spleen and gut IEL (Figure 2A, GEO accession GSE128147)
Summary
Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”[1] These retain functionality and home to peripheral organs, leading to interest in these cells in vaccination[1]. A subset of cytotoxic KLRG1+ effector memory CD8+ T-cells downregulate KLRG1 (“exKLRG1”) and differentiate into all memory T-cell lineages including CX3CR1int TPM and CX3CR1neg T cells[6] Persistent viruses such as murine cytomegalovirus (MCMV) and adenovirus-based vaccines induce strong, sustained CD8+ T-cell responses, described as memory “inflation”. These retain functionality, home to peripheral organs and are associated with a distinct transcriptional program. Conclusions: These data indicate that CD8+ T-cell memory in the gut epithelium induced by persistent viruses and vaccines has a distinct quality from both conventional memory and “inflationary” memory which may be relevant to protection against mucosal infections.
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