A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression
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Prolonged exposure of CD8+T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα+CD8+T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα+cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8+T cell-killing in vivo. SIRPα+CD8+T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+T cells during chronic infection expands the cytotoxic subset of SIRPα+CD8+T cells.
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Activated T cells also express SIRPa, and interaction with CD47 increases T cell activation and cytokine production, which may affect the clinical benefit of CD47 blockade.
“Recent studies revealed that activated T cells also express SIRPa and that interaction with CD47 results in increased T cell activation and cytokine production20, which may impact the potential clinical benefit of CD47-blockade21.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [20]
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- Authors
- Myers, L. M., Tal, M. C., Torrez Dulgeroff, L. B., Carmody, A. B., Messer, R. J., Gulati, G., Yiu, Y. Y., Staron, M. M., Angel, C. L., Sinha, R., Markovic, M., Pham, E. A., Fram, B., Ahmed, A., Newman, A. M., Glenn, J. S., Davis, M. M., Kaech, S. M., Weissman, I. L., & Hasenkrug, K. J.
- Affiliations
- Rocky Mountain Laboratories (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Stanford Medicine (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Hasenkrug, Kim J.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-02-15
- Volume
- 10
- Issue
- 1
- Pages
- 794-794
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6377614
- OpenAlex
- W2911813338
- Cited by
- 66
- References
- 81
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 16 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 11 · 2019: 5
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (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)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Virginia and D.K. Ludwig Fund for Cancer Research (U01HL099999)
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- National Institutes of Health (5u19ai109662-05, 1f32ai124558-01, ZA1000753, U19 AI109662, F32 AI124558-01)
- National Heart, Lung, and Blood Institute (U01HL099999)
- National Cancer Institute (R01CA086017, P30CA014195)
- National Institute of Allergy and Infectious Diseases (1 F32 AI124558-01, F32 AI124558, U19-AI109662, U19AI057229, T32AI007290)
- National Institute of Diabetes and Digestive and Kidney Diseases (F30DK099017)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CD8+ T cells, T cell exhaustion, SIRPα, CD47, chronic viral infection, co-inhibitory receptors, costimulatory receptors, interferon-gamma, cytotoxicity, PD-L1 blockade, hepatitis C virus, LCMV clone 13, T cell proliferation
- MeSH terms
- Animals, Arenaviridae Infections, Female, Humans, Lymphocyte Activation, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Immunologic, T-Lymphocytes, Cytotoxic, Gene Expression, CD8-Positive T-Lymphocytes, Gene Expression Profiling, Host-Pathogen Interactions
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