Neutrophils recruited by IL-22 in peripheral tissues function as TRAIL-dependent antiviral effectors against MCMV.
During primary infection, murine cytomegalovirus (MCMV) spreads systemically, resulting in virus replication and pathology in multiple organs. This disseminated infection is ultimately controlled, but the underlying immune defense mechanisms are unclear. Investigating the role of the cytokine IL-22 in MCMV infection, we discovered an unanticipated function for neutrophils as potent antiviral effector cells that restrict viral replication and associated pathogenesis in peripheral organs. NK-, NKT-, and T cell-secreted IL-22 orchestrated antiviral neutrophil-mediated responses via induction in stromal nonhematopoietic tissue of the neutrophil-recruiting chemokine CXCL1. The antiviral effector properties of infiltrating neutrophils were directly linked to the expression of TNF-related apoptosis-inducing ligand (TRAIL). Our data identify a role for neutrophils in antiviral defense, and establish a functional link between IL-22 and the control of antiviral neutrophil responses that prevents pathogenic herpesvirus infection in peripheral organs.
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Maria A
MA
Stacey
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Morgan
M
Marsden
Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1HH, UK.
Tu Anh
TA
Pham N
Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1HH, UK.
Simon
S
Clare
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Garry
G
Dolton
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Gabrielle
G
Stack
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Emma
E
Jones
Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
Paul
P
Klenerman
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Awen M
AM
Gallimore
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Philip R
PR
Taylor
Imperial College London, Leukocyte Biology Section, National Heart and Lung Institute, London SW7 2AZ, UK.
Robert J
RJ
Snelgrove
Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1HH, UK.
Trevor D
TD
Lawley
Microbial Pathogenesis Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1HH, UK.
Gordon
G
Dougan
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
Chris A
CA
Benedict
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Simon A
SA
Jones
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.
Gavin W G
GW
Wilkinson
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK. Electronic address: humphreysir@cardiff.ac.uk.
Ian R
IR
Humphreys
D000818:Animals; D000998:Antiviral Agents; D054360:Chemokine CXCL1 / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology; D007378:Interleukins / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology* / Q000472:pathogenicity; D055611:Natural Killer T-Cells / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D014779:Virus Replication / Q000276:immunology; D000097043:Interleukin-22
D000998:Antiviral Agents; D054360:Chemokine CXCL1; D007378:Interleukins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000097043:Interleukin-22; C475895:Cxcl1 protein, mouse; C505654:Tnfsf10 protein, mouse