title: Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.
abstract: BACKGROUND
  Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood.
  
  
  OBJECTIVE
  In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function.
  
  
  METHODS
  ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity.
  
  
  RESULTS
  We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model.
  
  
  CONCLUSIONS
  These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma.
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Diamanda
authors.initials: D
authors.lastname: Rigas
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif; Janssen Research and Development, San Diego, Calif.
authors.forename: Gavin
authors.initials: G
authors.lastname: Lewis
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Aron
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Bowen
authors.initials: B
authors.lastname: Wang
authors.affiliation: Janssen Research and Development, San Diego, Calif.
authors.forename: Homayon
authors.initials: H
authors.lastname: Banie
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Ishwarya
authors.initials: I
authors.lastname: Sankaranarayanan
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Galle-Treger
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Hadi
authors.initials: H
authors.lastname: Maazi
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Richard
authors.initials: R
authors.lastname: Lo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Mass.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston, Mass.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Janssen Research and Development, San Diego, Calif.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. Electronic address: akbari@usc.edu.
authors.forename: Omid
authors.initials: O
authors.lastname: Akbari
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D008214:Lymphocytes / Q000276:immunology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic
chemical_list: D016207:Cytokines
keywords: IL-13; IL-5; Type 2 innate lymphoid cells; airway hyperreactivity; asthma; inducible T-cell costimulator; inducible T-cell costimulator ligand; regulatory T cells