title: Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity.
abstract: BACKGROUND
  Asthma has been considered an immunologic disease mediated by T(H)2 cells and adaptive immunity. However, clinical and experimental observations suggest that additional pathways might regulate asthma, particularly in its nonallergic forms, such as asthma associated with air pollution, stress, obesity, and infection.
  
  
  OBJECTIVE
  Our goal was to understand T(H)2 cell-independent conditions that might lead to airway hyperreactivity (AHR), a cardinal feature of asthma.
  
  
  METHODS
  We examined a murine model of experimental asthma in which AHR was induced with glycolipid antigens, which activate natural killer T (NKT) cells.
  
  
  RESULTS
  In this model AHR developed rapidly when mice were treated with NKT cell-activating glycolipid antigens, even in the absence of conventional CD4(+) T cells. The activated NKT cells directly induced alveolar macrophages to produce IL-33, which in turn activated NKT cells, as well as natural helper cells, a newly described non-T, non-B, innate lymphoid cell type, to increase production of IL-13. Surprisingly, this glycolipid-induced AHR pathway required not only IL-13 but also IL-33 and its receptor, ST2, because it was blocked by an anti-ST2 mAb and was greatly reduced in ST2(-/-) mice. When adoptively transferred into IL-13(-/-) mice, both wild-type natural helper cells and NKT cells were sufficient for the development of glycolipid-induced AHR.
  
  
  CONCLUSIONS
  Because plant pollens, house dust, and some bacteria contain glycolipids that can directly activate NKT cells, these studies suggest that AHR and asthma can fully develop or be greatly enhanced through innate immune mechanisms involving IL-33, natural helper cells, and NKT cells.
authors: Division of Immunology and Allergy, Children's Hospital, Harvard Medical School, Boston, Mass, USA.
authors: Hye Young
authors: HY
authors: Kim
authors: Ya-Jen
authors: YJ
authors: Chang
authors: Srividya
authors: S
authors: Subramanian
authors: Hyun-Hee
authors: HH
authors: Lee
authors: Lee A
authors: LA
authors: Albacker
authors: Ponpan
authors: P
authors: Matangkasombut
authors: Paul B
authors: PB
authors: Savage
authors: Andrew N J
authors: AN
authors: McKenzie
authors: Dirk E
authors: DE
authors: Smith
authors: James B
authors: JB
authors: Rottman
authors: Rosemarie H
authors: RH
authors: DeKruyff
authors: Dale T
authors: DT
authors: Umetsu
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage; D006017:Glycolipids / Q000276:immunology; D007113:Immunity, Innate; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000096:biosynthesis; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D020578:Sphingomonas / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D005699:Galactosylceramides; D006017:Glycolipids; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin