title: T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death.
abstract: BACKGROUND
  Studies of asthma have been limited by a poor understanding of how nonallergic environmental exposures, such as air pollution and infection, are translated in the lung into inflammation and wheezing.
  
  
  OBJECTIVE
  Our goal was to understand the mechanism of nonallergic asthma that leads to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity.
  
  
  METHODS
  We examined mouse models of experimental asthma in which AHR was induced by respiratory syncytial virus infection or ozone exposure using mice deficient in T-cell immunoglobulin and mucin domain 1 (TIM1/HAVCR1), an important asthma susceptibility gene.
  
  
  RESULTS
  TIM1(-/-) mice did not have airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1(-/-) mice had allergen-induced experimental asthma, as previously shown. The RSV- and ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of AHR.
  
  
  CONCLUSIONS
  We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells.
authors.affiliation: Division of Immunology and Allergy, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Ya-Jen
authors.initials: YJ
authors.lastname: Chang
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chuang
authors.forename: Hyun-Hee
authors.initials: HH
authors.lastname: Lee
authors.forename: David I
authors.initials: DI
authors.lastname: Kasahara
authors.forename: Thomas
authors.initials: T
authors.lastname: Martin
authors.forename: Joyce T
authors.initials: JT
authors.lastname: Hsu
authors.forename: Paul B
authors.initials: PB
authors.lastname: Savage
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shore
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: Dekruyff
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D001980:Bronchi / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology; D010126:Ozone / Q000009:adverse effects; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D010126:Ozone
keywords: AHR; Airway hyperreactivity; BAL; Bronchoalveolar lavage; NKT; Natural killer T; OVA; Ovalbumin; Phosphatidylserine; PtdSer; RSV; Respiratory syncytial virus; T-cell immunoglobulin and mucin domain; TIM; TIM-1; TUNEL; Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling; WT; Wild-type; apoptosis; asthma; natural killer T; α-GalCer; α-Galactosylceramide