Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Massoud, Amir H.^1,2,3  Yona, Madelaine^1,2  Xue, Di^1,2  Chouiali, Fazila^1,2  Alturaihi, Haydar³  Ablona, Aidan^1,2  Mourad, Walid³  Piccirillo, Ciriaco A.⁴  Mazer, Bruce D.^1,2 

[1] McGill Univ, Meakins Christie Labs, Dept Pediat, Div Allergy & Immunol,Res Inst,Hlth Ctr, Montreal, PQ H2X 2P2, Canada

[2] McGill Univ, Dept Med, Montreal, PQ H2X 2P2, Canada

[3] Univ Montreal, Inst Rech, Hop St Luc, Dept Immunol & Microbiol, Montreal, PQ, Canada

[4] McGill Univ, Res Inst, Dept Microbiol & Immunol, Ctr Hlth, Montreal, PQ H2X 2P2, Canada

关键词: Intravenous immunoglobulin;    dendritic cells;    regulatory T cells;    immune modulation;    asthma;   

DOI  :  10.1016/j.jaci.2013.09.029

来源: Elsevier

【 摘 要 】

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 Fc gamma receptor knockout mice inhibited AHR, suggesting IVIg's action was not caused by Fc gamma 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.

【 授权许可】

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