title: Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells.
abstract: BACKGROUND
  Intravenous immunoglobulin (IVIg) is a polyclonal IgG preparation with potent immunomodulating properties. Our laboratory demonstrated that IVIg significantly increases numbers of forkhead box protein 3-positive regulatory T (Treg) cells through generation of tolerogenic dendritic cells (DCs) in an allergic airways disease model.
  
  
  OBJECTIVE
  We sought to investigate potential receptors on DCs mediating these events.
  
  
  METHODS
  C57BL/6 mice were either sensitized to ovalbumin (OVA) intraperitoneally or through adoptive transfer of OVA-primed DCs and then challenged with intranasal OVA. IVIg was fractionated into sialic acid-enriched IVIg (SA-IVIg) and sialic acid-depleted IVIg (non-SA-IVIg). Dendritic cell immunoreceptor (DCIR) constructs in CHO cells or on DCs were examined by using fluorescent microscopy and flow cytometry.
  
  
  RESULTS
  Administration of SA-IVIg, but not non-SA-IVIg, to OVA-sensitized and OVA-challenged mice induced Treg cells and attenuated airway hyperresponsiveness (AHR) and inflammation comparably with IVIg. Bone marrow-derived dendritic cells cultured with SA-IVIg or IVIg adoptively transferred to mice before OVA challenge induced Treg cells and inhibited AHR. IVIg-treated bone marrow-derived dendritic cells from Fcγ receptor knockout mice inhibited AHR, suggesting IVIg's action was not caused by Fcγ receptor-mediated events. Fluorescently labeled IVIg or SA-IVIg bound DCs and colocalized specifically to the C-type lectin DCIR. IVIg binding to DCIR induced phosphorylation of Src homology domain 2-containing protein tyrosine phosphatase (SHP) 2 and Src homology domain 2-containing inositol phosphatase 1 (SHIP-1) and internalization of IVIg into DCs. Inhibition of IVIg binding to DCIR by small interfering RNA completely blocked induction of Treg cells. Inhibition of SHP-2 or abrogation of IgG internalization through clatherin inhibitors rendered IVIg ineffective.
  
  
  CONCLUSIONS
  IVIg alleviates allergic airways disease through interaction of SA-IgG with DCIR. DCIR is a novel receptor for IVIg, mediating interaction of innate and adaptive immunity in tolerogenic responses.
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada; Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada.
authors.forename: Amir H
authors.initials: AH
authors.lastname: Massoud
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Madelaine
authors.initials: M
authors.lastname: Yona
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Di
authors.initials: D
authors.lastname: Xue
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Fazila
authors.initials: F
authors.lastname: Chouiali
authors.affiliation: Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada.
authors.forename: Haydar
authors.initials: H
authors.lastname: Alturaihi
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Aidan
authors.initials: A
authors.lastname: Ablona
authors.affiliation: Département d'Immunologie et Microbiologie, Université de Montréal, Institute de Recherche du l'Hôpitale St-Luc, Montreal, Quebec, Canada.
authors.forename: Walid
authors.initials: W
authors.lastname: Mourad
authors.affiliation: Department of Microbiology and Immunology, The Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.affiliation: Meakins Christie Laboratories, the Department of Pediatrics, Division of Allergy and Immunology, The Research Institute of the McGill University Health Center, and the Department of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: bruce.mazer@mcgill.ca.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Mazer
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000517:prevention & control; D016466:CHO Cells; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D037181:Lectins, C-Type / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C423004:CLEC4A protein, human; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D010047:Ovalbumin; D010744:Phosphoric Monoester Hydrolases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: Intravenous immunoglobulin; asthma; dendritic cells; immune modulation; regulatory T cells