title: Antigen-sensitized CD4+CD62Llow memory/effector T helper 2 cells can induce airway hyperresponsiveness in an antigen free setting.
abstract: BACKGROUND
  Airway hyperresponsiveness (AHR) is one of the most prominent features of asthma, however, precise mechanisms for its induction have not been fully elucidated. We previously reported that systemic antigen sensitization alone directly induces AHR before development of eosinophilic airway inflammation in a mouse model of allergic airway inflammation, which suggests a critical role of antigen-specific systemic immune response itself in the induction of AHR. In the present study, we examined this possibility by cell transfer experiment, and then analyzed which cell source was essential for this process.
  
  
  METHODS
  BALB/c mice were immunized with ovalbumin (OVA) twice. Spleen cells were obtained from the mice and were transferred in naive mice. Four days later, AHR was assessed. We carried out bronchoalveolar lavage (BAL) to analyze inflammation and cytokine production in the lung. Fluorescence and immunohistochemical studies were performed to identify T cells recruiting and proliferating in the lung or in the gut of the recipient. To determine the essential phenotype, spleen cells were column purified by antibody-coated microbeads with negative or positive selection, and transferred. Then, AHR was assessed.
  
  
  RESULTS
  Transfer of spleen cells obtained from OVA-sensitized mice induced a moderate, but significant, AHR without airway antigen challenge in naive mice without airway eosinophilia. Immunization with T helper (Th) 1 elicited antigen (OVA with complete Freund's adjuvant) did not induce the AHR. Transferred cells distributed among organs, and the cells proliferated in an antigen free setting for at least three days in the lung. This transfer-induced AHR persisted for one week. Interleukin-4 and 5 in the BAL fluid increased in the transferred mice. Immunoglobulin E was not involved in this transfer-induced AHR. Transfer of in vitro polarized CD4+ Th2 cells, but not Th1 cells, induced AHR. We finally clarified that CD4+CD62Llow memory/effector T cells recruited in the lung and proliferated, thus induced AHR.
  
  
  CONCLUSIONS
  These results suggest that antigen-sensitized memory/effector Th2 cells themselves play an important role for induction of basal AHR in an antigen free, eosinophil-independent setting. Therefore, regulation of CD4+ T cell-mediated immune response itself could be a critical therapeutic target for allergic asthma.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. nakagomek-tky@umin.ac.jp
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.forename: Makoto
authors.initials: M
authors.lastname: Dohi
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: To
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Komagata
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagatani
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D007114:Immunization; D019041:L-Selectin / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D013154:Spleen / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology*
chemical_list: D019041:L-Selectin; D010047:Ovalbumin