Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner
Open accessAbstract
Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity.
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TVM cells express high levels of CD122 and NK cell markers, both of which increase with age and would otherwise be misattributed to Tcm cells.
“In addition, TVM cells express high levels of CD122 and NK cell markers, both of which increase with age and would otherwise be misattributed to Tcm cells [354, 356].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [356]
The Results section, “Phenotypic similarities in putative human VM cells” (page unavailable), describes high CD122 expression and KIR/NKG2A markers in putative VM cells, and reports that the frequency of these marker-positive cells correlates with age. It does not show that each marker’s expression increases with age or say these cells would otherwise be attributed to central memory T (Tcm) cells; it describes the putative human subset as previously considered terminal effector memory RA+. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAs people age, CD8+ T cells can lose their naive quiescent state and differentiate in response to IL-15 signaling without cognate antigen.
“As we age, CD8+ T cells can also lose their naive quiescent state and differentiate in response to IL-15 signaling without the presence of their cognate antigen.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [147]
A human equivalent of virtual memory CD8+ T cells (CD45RA+KIR+NKG2A+Eomes+) has been identified and positively correlates with age.
“These ‘virtual memory’ CD8+ T cells have been most widely studied in mice147, but a human equivalent population has been identified (CD45RA+KIR+NKG2A+Eomes+) and similarly positively correlates with age147.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [147]
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- Authors
- White, J. T., Cross, E. W., Burchill, M. A., Danhorn, T., McCarter, M. D., Rosen, H. R., O’Connor, B., & Kedl, R. M.
- Affiliations
- University of Colorado Anschutz (US)
- National Jewish Health (US)
- Corresponding author
- Kedl, Ross M.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-04-21
- Volume
- 7
- Issue
- 1
- Pages
- 11291-11291
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4844673
- OpenAlex
- W2338528249
- Cited by
- 219
- References
- 58
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 25 · 2023: 30 · 2022: 17 · 2021: 36 · 2020: 28 · 2019: 15 · 2018: 17 · 2017: 9 · 2016: 2
- FWCI
- 8.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (T32GM008497)
- National Institute of Allergy and Infectious Diseases (R01AI101205, R01AI066121)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- virtual memory T cells, CD8+ T cells, homeostatic proliferation, IL-15, bystander killing, protective immunity, naive T cells, aging, gene expression profiling
- MeSH terms
- Adult, Aged, Animals, Autoantigens, Cell Movement, Female, Homeostasis, Humans, Immunity, Innate, Immunologic Memory, Liver, Male, Mice, Inbred C57BL, Middle Aged, Spleen, Signal Transduction, Gene Expression, Mice, Knockout, CD8-Positive T-Lymphocytes, Interleukin-15, Bystander Effect, Cell Proliferation, Mice, Primary Cell Culture
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