IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection

• Published in: PloS one Vol. 10; no. 4; p. e0120169
• Main Authors: Moser, Emily K, Sun, Jie, Kim, Taeg S, Braciale, Thomas J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.04.2015; Public Library of Science (PLoS)
• Subjects: Alveoli; Animals; Bronchoalveolar Lavage Fluid - chemistry; Bronchus; Cells, Cultured; Chronic infection; Cytokines; Cytokines - genetics; Cytokines - metabolism; Female; Flow Cytometry; Helper cells; Immune clearance; Immune response; Immune system; Immunomodulation; Inflammation; Influenza; Influenza A; Influenza A virus - immunology; Influenza A virus - pathogenicity; Interleukin 17; Interleukin 21; Interleukin-17 - genetics; Interleukin-17 - metabolism; Lung - immunology; Lung - pathology; Lung - virology; Lungs; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - virology; Real-Time Polymerase Chain Reaction; Receptors, Antigen, T-Cell, gamma-delta - genetics; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Receptors, Interleukin-21 - physiology; Respiratory tract; Respiratory tract diseases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signaling; Steady state; Th17 Cells - immunology; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0120169

Influenza A virus (IAV) infection of the respiratory tract elicits a robust immune response, which is required for efficient virus clearance but at the same time can contribute to lung damage and enhanced morbidity. IL-21 is a member of the type I cytokine family and has many different immune-modulatory functions during acute and chronic virus infections, although its role in IAV infection has not been fully evaluated. In this report we evaluated the contributions of IL-21/IL-21 receptor (IL-21R) signaling to host defense in a mouse model of primary IAV infection using IL-21R knock out (KO) mice. We found that lack of IL-21R signaling had no significant impact on virus clearance, adaptive T cell responses, or myeloid cell accumulations in the respiratory tract. However, a subset of inflammatory cytokines were elevated in the bronchoalveolar lavage fluid of IL-21R KO mice, including IL-17. Although there was only a small increase in Th17 cells in the lungs of IL-21R KO mice, we observed a dramatic increase in gamma delta (γδ) T cells capable of producing IL-17 both after IAV infection and at steady state in the respiratory tract. Finally, we found that IL-21R signaling suppressed the accumulation of IL-17+ γδ T cells in the respiratory tract intrinsically. Thus, our study reveals a previously unrecognized role of IL-21R signaling in regulating IL-17 production by γδ T cells.