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

https://doi.org/10.1016/j.jaci.2013.09.029Get rights and content

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.

Section snippets

Fractionation of IVIg

Fractionation of IVIg was performed by using Sambucus nigra agglutinin–lectin affinity columns, according to the manufacturer’s protocol. IVIg (Talecris Biotherapeutics, Mississauga, Ontario, Canada) was loaded onto a 2-mL Sambucus nigra agglutinin column. The flow-through fraction (sialic acid–depleted intravenous immunoglobulin [non-SA-IVIg]) was collected by washing the column with 10 mL of Tris-buffered saline. The SA-IVIg fraction was eluted by using 4 mL of 0.5 mol/L lactose. The

Sialylated IgG is required for the anti-inflammatory effect of IVIg

IVIg, SA-IVIg, or non-SA-IVIg were administered to OVA-sensitized mice 1 day before allergen challenge to address whether sialylated IgG attenuates allergic airways disease (AAD). SA-IVIg attenuated MCh-induced AHR in OVA-challenged mice comparable with intact IVIg (Fig 1, A) at a 10-fold lower dose. Inhibition of AHR by IVIg and SA-IVIg was accompanied by a significant increase in the frequency of Treg cells within the lungs (Fig 1, B and C). Administration of non-SA-IVIg did not prevent

Discussion

IgG is a crucial effector molecule in host defense recognized for its role in pathogen elimination and autoimmune diseases. However, there are many examples of IgG contributing to immune tolerance, and IVIg is frequently used as disease-modifying therapy for autoimmune and inflammatory conditions.17 Using a murine model of AAD, we reported that high-dose IVIg induces Foxp3+ Treg cells from Foxp3CD4+ T cells, attenuating allergen-induced AHR. The effect of IVIg is the result of functional

References (41)

  • N. Kanazawa

    Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells

    J Dermatol Sci

    (2007)
  • A.A. Lambert et al.

    The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways

    Blood

    (2008)
  • T.L. Hsu et al.

    Profiling carbohydrate-receptor interaction with recombinant innate immunity receptor-Fc fusion proteins

    J Biol Chem

    (2009)
  • D.P. Proulx et al.

    Spontaneous internalization of IVIg in activated B cells

    Immunol Lett

    (2009)
  • E. Aubin et al.

    Prevention of T cell activation by interference of internalized intravenous immunoglobulin (IVIg) with MHC II-dependent native antigen presentation

    Clin Immunol

    (2011)
  • E. Gonzalez-Rey et al.

    Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells

    Blood

    (2006)
  • A. Ephrem et al.

    Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

    Blood

    (2008)
  • R. Aslam et al.

    Thymic retention of CD4+CD25+FoxP3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia

    Blood

    (2012)
  • A.S. De Groot et al.

    Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes

    Blood

    (2008)
  • J.N. Arnold et al.

    The impact of glycosylation on the biological function and structure of human immunoglobulins

    Annu Rev Immunol

    (2007)
  • Cited by (122)

    • An integrated method for IgG N-glycans enrichment and analysis: Understanding the role of IgG glycosylation in diabetic foot ulcer

      2024, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
    • Intravenous Immunoglobulin: Mechanism of Action in Autoimmune and Inflammatory Conditions

      2023, Journal of Allergy and Clinical Immunology: In Practice
    • Sialylated IVIg binding to DC-SIGN<sup>+</sup> Hofbauer cells induces immune tolerance through the caveolin-1/NF-kB pathway and IL-10 secretion

      2023, Clinical Immunology
      Citation Excerpt :

      In a mechanical analysis of the roles of IVIg, Ravetch et al. revealed that the anti-inflammatory activity of IVIg is mediated mainly by immunoglobulins containing terminal α-2,6-sialic acid linkages at the Asn297-linked glycan of the Fc region (sIVIg) [18]. Several preclinical model systems have provided evidence of the important role of sIVIg in determining the therapeutic activity of IVIg in rheumatoid arthritis, allergic airway disease, and autoimmune neurological disorders [19–22]. Therefore, sIVIg is considered a critical therapeutic strategy for attenuating pathogenic autoimmunity.

    • Antibody glycosylation directs innate and adaptive immune collaboration

      2022, Current Opinion in Immunology
      Citation Excerpt :

      Sialylated antibodies have an anti-inflammatory effect. A number of research groups have proposed different mechanisms for this effect (Figure 1) thus it is not yet precisely clear how sialylation induces an anti-inflammatory bias [23–26]. Specific trends in antibody glycosylation have been identified in numerous contexts such as age, pregnancy, vaccination, infection, and autoimmune diseases [18].

    • Immunoglobulin Therapy: Replacement and Immunomodulation

      2022, Clinical Immunology: Principles and Practice, Sixth Edition
    View all citing articles on Scopus

    Supported by Talecris and Grifols Bio-therapeutics (Clinical Investigation Program) and the Canadian Institutes for Health Research (CIHR grants ISO115295 [to B.D.M.] and MOP67211 [to C.A.P.]), The Research Institute of the McGill University Health Center (RI-MUHC), the Montreal Chest Institute, and the Strauss Family Foundation. A.H.M. was the recipient of a Fonds de Recherche en Santé du Québec (FRSQ) Student Scholarship. B.D.M. is a Chercheur National of the FRSQ. C.A.P. holds a CIHR Canada Research Chair.

    Disclosure of potential conflict of interest: A. H. Massoud has received research support from the Canadian Institute for Health Research (CIHR). F. Chouiali has received research support. H. Alturaihi has received research support from CIHR. C. A. Piccirillo has received consultant fees from GlaxoSmithKline, is employed by McGill University and Research Institute MUHC, and has provided expert testimony for the Montreal Law Firm. B. D. Mazer has received grants from Grifols Biotherapeutics and the CIHR and has grants/grants pending and has received payment for lectures including service on speakers' bureaus from Novartis. The rest of the authors declare that they have no relevant conflicts of interest.

    View full text