Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3-positive regulatory T cells

Background: Intravenous immunoglobulin (IVIG) is a frequently used disease-modifying therapy for a large spectrum of autoimmune and inflammatory conditions, yet its mechanisms of action are incompletely understood. Using a robust murine model of antigen-driven allergic airways disease, we have demonstrated that IVIG markedly improves ovalbumin (OVA)-induced airway hyperresponsiveness characterized by 4- to 6-fold enhancement in regulatory T (Treg) cells in pulmonary and associated lymphoid tissues. Objective: We sought to determine whether IVIG induces antigen-specific Treg cells and to address cellular interactions that lead to induction of Treg cells by IVIG. Methods: C57Bl/6 mice were sensitized and challenged by means of intranasal OVA exposure. IVIG or albumin control was administered 24 hours before challenge. Treg cells were tracked by using green fluorescent protein (GFP)-forkhead box protein 3 (Foxp3) knock-in reporter mice (Foxp3(GFP)), and Treg cell and dendritic cell (DC) phenotypes and activities were elucidated by using coculture and flow cytometry. Results: IVIG therapy of OVA-sensitized and OVA-challenged mice induced antigen-specific forkhead box protein 3 (Foxp3)-positive Treg cells from non-Treg cell precursors. The induced Treg cells home specifically to the lungs and draining lymph nodes and have greatly potentiated suppressive activity compared with that seen in Treg cells purified from control mice. Induction of Treg cells is mediated by tolerogenic DCs generated after IVIG exposure. Compared with albumin-treated, OVA-exposed mice, IVIG-primed DCs express altered Notch ligands, including increased Delta-4 and reduced Jagged-1 levels, reflecting decreased T(H)2 polarization. Furthermore, IVIG-primed DCs can stimulate Treg cell differentiation from uncommitted Foxp3(-) CD4(+) T cells ex vivo, and adoptive transfer of IVIG-primed DCs abrogates airway hyperresponsiveness and induces Treg cells. Conclusion: The anti-inflammatory effects of IVIG therapy can be mediated by the immunomodulation of DCs, creating a bridge that induces antigen-specific, highly suppressive Treg cells. (J Allergy Clin Immunol 2012;129:1656-65.)