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Nat Commun. 2019 Feb 15;10(1):794. doi: 10.1038/s41467-019-08637-9.

A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPα expression.

Author information

1
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, MT, 59840, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
3
Research Technologies Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, 59840, USA.
4
Foundational Immunology, AbbVie Bioresearch Center, Worcester, MA, 01605, USA.
5
Deparment of Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
6
Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
7
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, 94305, USA.
8
Deparment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
9
Department of Immunobiology, Yale School of Medicine, New Haven, CT, 06520, USA.
10
NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, La Jolla, CA, 92037, USA.
11
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, MT, 59840, USA. khasenkrug@nih.gov.

Abstract

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.

PMID:
30770827
PMCID:
PMC6377614
DOI:
10.1038/s41467-019-08637-9
[Indexed for MEDLINE]
Free PMC Article

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