title: IL-21 promotes the pathologic immune response to pneumovirus infection.
abstract: IL-21 is a cytokine with pleiotropic actions, promoting terminal differentiation of B cells, increased Ig production, and the development of Th17 and T follicular helper cells. IL-21 is also implicated in the development of autoimmune disease and has antitumor activity. In this study, we investigated the role of IL-21 in host defense to pneumonia virus of mice (PVM), which initiates an infection in mice resembling that of respiratory syncytial virus disease in humans. We found that PVM-infected mice expressed IL-21 in lung CD4(+) T cells. Following infection, Il21r(-/-) mice exhibited less lung infiltration by neutrophils than did wild-type (WT) mice and correspondingly had lower levels of the chemokine CXCL1 in bronchoalveolar lavage fluid and lung parenchyma. CD8(+), CD4(+), and γδ T cell numbers were also lower in the lungs of PVM-infected Il21r(-/-) mice than in infected WT mice, with normal Th17 cytokines but diminished IL-6 production in PVM-infected Il21r(-/-) mice. Strikingly, Il21r(-/-) mice had enhanced survival following PVM infection, and moreover, treatment of WT mice with soluble IL-21R-Fc fusion protein enhanced their survival. These data reveal that IL-21 promotes the pathogenic inflammatory effect of PVM and indicate that manipulating IL-21 signaling may represent an immunomodulatory strategy for controlling PVM and potentially other respiratory virus infections.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Chi-Keung
authors.initials: CK
authors.lastname: Wan
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Bonville
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Domachowske
authors.forename: Hyoung-Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Zuxi
authors.initials: Z
authors.lastname: Yu
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054360:Chemokine CXCL1 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D029122:Murine pneumonia virus / Q000276:immunology* / Q000472:pathogenicity; D018186:Pneumovirus Infections / Q000276:immunology* / Q000473:pathology*; D053655:Receptors, Interleukin-21 / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D054360:Chemokine CXCL1; D015850:Interleukin-6; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21