title: Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response.
abstract: We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells--which are associated with enhanced RSV disease--and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Shirin
authors.initials: S
authors.lastname: Munir
authors.forename: Philippa
authors.initials: P
authors.lastname: Hillyer
authors.forename: Cyril
authors.initials: C
authors.lastname: Le Nouën
authors.forename: Ursula J
authors.initials: UJ
authors.lastname: Buchholz
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Rabin
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Alexander
authors.initials: A
authors.lastname: Bukreyev
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D039001:Integrin alpha Chains; D017361:Viral Nonstructural Proteins; C091367:alpha E integrins; D007372:Interferons