Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity.

Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment.

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

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.