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; Kim J Hasenkrug

doi:10.1038/s41467-019-08637-9

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

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

Authors

Lara M Myers¹, Michal Caspi Tal², Laughing Bear Torrez Dulgeroff², Aaron B Carmody³, Ronald J Messer¹, Gunsagar Gulati², Ying Ying Yiu², Matthew M Staron^{3

4}, Cesar Lopez Angel⁵, Rahul Sinha², Maxim Markovic², Edward A Pham^{2

6}, Benjamin Fram⁶, Aijaz Ahmed⁶, Aaron M Newman^{2

7}, Jeffrey S Glenn^{6

8}, Mark M Davis⁸, Susan M Kaech^{9

10}, Irving L Weissman², Kim J Hasenkrug¹¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arenaviridae Infections / genetics
Arenaviridae Infections / immunology*
Arenaviridae Infections / virology
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / virology
Female
Gene Expression / immunology
Gene Expression Profiling
Host-Pathogen Interactions / immunology
Humans
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology
Lymphocytic Choriomeningitis / genetics
Lymphocytic Choriomeningitis / immunology*
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology*
Lymphocytic choriomeningitis virus / physiology
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Immunologic / genetics
Receptors, Immunologic / immunology*
Receptors, Immunologic / metabolism
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
T-Lymphocytes, Cytotoxic / virology

Substances

Ptpns1 protein, mouse
Receptors, Immunologic

Abstract

Publication types

MeSH terms

Substances

Grants and funding