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

Lara M. Myers, Michal Caspi Tal, Laughing Bear Torrez Dulgeroff, Aaron B. Carmody, Ronald J. Messer, Gunsagar Gulati, Ying Ying Yiu, Matthew M. Staron, Cesar Lopez Angel, Rahul Sinha, Maxim Markovic, Edward A. Pham, Benjamin Fram, Aijaz Ahmed, Aaron M. Newman, Jeffrey S. Glenn, Mark M. Davis, Susan M. Kaech, Irving L. Weissman and Kim J. Hasenkrug ()
Additional contact information
Lara M. Myers: Rocky Mountain Laboratories
Michal Caspi Tal: Stanford University School of Medicine
Laughing Bear Torrez Dulgeroff: Stanford University School of Medicine
Aaron B. Carmody: Rocky Mountain Laboratories, NIAID, NIH
Ronald J. Messer: Rocky Mountain Laboratories
Gunsagar Gulati: Stanford University School of Medicine
Ying Ying Yiu: Stanford University School of Medicine
Matthew M. Staron: Rocky Mountain Laboratories, NIAID, NIH
Cesar Lopez Angel: Stanford University School of Medicine
Rahul Sinha: Stanford University School of Medicine
Maxim Markovic: Stanford University School of Medicine
Edward A. Pham: Stanford University School of Medicine
Benjamin Fram: Stanford University School of Medicine
Aijaz Ahmed: Stanford University School of Medicine
Aaron M. Newman: Stanford University School of Medicine
Jeffrey S. Glenn: Stanford University School of Medicine
Mark M. Davis: Stanford University School of Medicine
Susan M. Kaech: Yale School of Medicine
Irving L. Weissman: Stanford University School of Medicine
Kim J. Hasenkrug: Rocky Mountain Laboratories

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08637-9

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