title: Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma.
abstract: Immune tolerance is instituted early in life, during which time regulatory T (T(reg)) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother's milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (T(H)2) cytokine production in forkhead box P3 (FOXP3)(+) T(reg) cells and compromised the suppressive function of pulmonary T(reg) cells in a manner that was dependent on interleukin-4 receptor α (IL-4Rα) expression in the host. Thus, by promoting a T(H)2-type inflammatory response in the lung, RSV induced a T(H)2-like effector phenotype in T(reg) cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.forename: Mahesh
authors.initials: M
authors.lastname: Raundhal
authors.forename: Christina
authors.initials: C
authors.lastname: Morse
authors.forename: Manohar
authors.initials: M
authors.lastname: Yarlagadda
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000821:virology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; D007073:Immunoglobulin E; D010047:Ovalbumin