title: Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells.
abstract: BACKGROUND
  Activation of the group 2 innate lymphoid cell (ILC2) population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), a receptor for prostaglandin D₂ (PGD₂), is expressed by human ILC2s. However, the function of CRTH2 in these cells is unclear.
  
  
  OBJECTIVE
  We sought to determine the role of PGD₂ and CRTH2 in human ILC2s and compare it with that of the established ILC2 activators IL-25 and IL-33.
  
  
  METHODS
  The effects of PGD₂, IL-25, and IL-33 on the cell migration, cytokine production, gene regulation, and receptor expression of ILC2s were measured with chemotaxis, ELISA, Luminex, flow cytometry, quantitative RT-PCR, and QuantiGene assays. The effects of PGD₂ under physiologic conditions were evaluated by using the supernatant from activated mast cells.
  
  
  RESULTS
  PGD₂ binding to CRTH2 induced ILC2 migration and production of type 2 cytokines and many other cytokines. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA). The effects of PGD₂ on ILC2s could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist.
  
  
  CONCLUSIONS
  PGD₂ is an important and potent activator of ILC2s through CRTH2 mediating strong proallergic inflammatory responses. Through IgE-mediated mast cell degranulation, these innate cells can also contribute to adaptive type 2 immunity; thus CRTH2 bridges the innate and adaptive pathways in human ILC2s.
authors.affiliation: Oxford NIHR Biomedical Research Centre, Translational Immunology Laboratory, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Electronic address: luzheng.xue@ndm.ox.ac.uk.
authors.forename: Luzheng
authors.initials: L
authors.lastname: Xue
authors.affiliation: Oxford NIHR Biomedical Research Centre, Translational Immunology Laboratory, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Salimi
authors.affiliation: Oxford NIHR Biomedical Research Centre, Translational Immunology Laboratory, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Panse
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Mjösberg
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.affiliation: Oxford NIHR Biomedical Research Centre, Translational Immunology Laboratory, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Peter Medawar Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. Electronic address: paul.klenerman@medawar.ox.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Oxford NIHR Biomedical Research Centre, Translational Immunology Laboratory, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Ogg
mesh_terms: D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
keywords: Group 2 innate lymphoid cell; IL-25; IL-33; PGD(2); adaptive type 2 immunity; chemoattractant receptor-homologous molecule expressed on T(H)2 cells; innate type 2 immunity