title: Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production.
abstract: BACKGROUND
  Cysteinyl leukotrienes (CysLTs) contribute to asthma pathogenesis, in part through cysteinyl leukotriene receptor 1 (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2s) potently produce IL-5 and IL-13.
  
  
  OBJECTIVE
  We hypothesized that lung ILC2s might be activated by leukotrienes through CysLT1R.
  
  
  METHODS
  ILC2s (Thy1.2(+) lineage-negative lymphocytes) and CysLT1R were detected in the lungs of wild-type, signal transducer and activator of transcription 6-deficient (STAT6(-/-)), and recombination-activating gene 2-deficient (RAG2(-/-)) mice by means of flow cytometry. T(H)2 cytokine levels were measured in purified lung ILC2s stimulated with leukotriene D₄ (LTD₄) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by using Fluo-4 intensity. Intranasal leukotriene C₄, D₄, and E₄ were administered to naive mice, and levels of ILC2 IL-5 production were determined. Finally, LTD₄ was coadministered with Alternaria species repetitively to RAG2(-/-) mice (with ILC2s) and IL-7 receptor-deficient mice (lack ILC2s), and total ILC2 numbers, proliferation (Ki-67(+)), and bronchoalveolar lavage fluid eosinophil numbers were measured.
  
  
  RESULTS
  CysLT1R was expressed on lung ILC2s from wild-type, RAG2(-/-), and STAT6(-/-) naive and Alternaria species-challenged mice. In vitro LTD₄ induced ILC2s to rapidly generate high levels of IL-5 and IL-13 within 6 hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2s. LTD₄ administered in vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast before treatment. Finally, LTD₄ potentiated Alternaria species-induced eosinophilia, as well as ILC2 accumulation and proliferation.
  
  
  CONCLUSIONS
  We present novel data that CysLT1R is expressed on ILC2s and LTD₄ potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD₄ potentiates Alternaria species-induced eosinophilia and ILC2 proliferation and accumulation.
authors.affiliation: Department of Medicine, University of California, La Jolla, CA 92093-0635, USA. tdoherty@ucsd.edu
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Naseem
authors.initials: N
authors.lastname: Khorram
authors.forename: Sean
authors.initials: S
authors.lastname: Lund
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Mehta
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D000528:Alternaria / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018077:Receptors, Leukotriene / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D018077:Receptors, Leukotriene; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D017998:Leukotriene D4; C083169:leukotriene D4 receptor