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Induction of Type 2 T Helper Cell Allergen Tolerance by IL-10–Differentiated Regulatory Dendritic Cells

¹ Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada; ² National Vaccine and Serum Institute, Beijing, China; and ³ Division of Respirology, Critical Care, and Sleep Medicine, Royal University Hospital, Saskatoon, Canada

Correspondence and requests for reprints should be addressed to John R. Gordon, Ph.D., Rm 3610, Royal University Hospital, 103 Hospital Drive, Box 120 R.U.H., Saskatoon, SK, Canada S7N 0W8. E-mail: john.gordon{at}usask.ca

In mouse models of asthma, therapeutic use of allergen-presenting IL-10–differentiated dendritic cells (DCs) can abrogate airway hyperresponsiveness, and reduce other asthma-related responses to near background. Analogous human DCs can suppress human T cell responses in vitro, but the operative mechanisms are poorly defined. We investigated the ability of IL-10–treated human DCs to induce tolerance among autologous T cells of subjects with asthma and the mechanisms by which they do this. CD14⁺ monocyte-derived DCs were differentiated in the presence of IL-10 (DC10) ex vivo from 11 donors with asthma and 4 control donors, and characterized for relevant markers. They were pulsed with specific or irrelevant allergen, and cultured with autologous peripheral blood CD4⁺ T cells, either alone or together with autologous immunostimulatory DCs (DC-TNF), and the impact of this treatment on the T-cell responses was assessed for each donor. The DC10 expressed reduced levels of some relevant markers (CD40, CD80, human leukocyte antigen-DR) and stimulatory cytokines (IL-6 and IL-12), but augmented levels of Ig-like transcript-22/CD85j and IL-10 relative to DC-TNF. In cocultures, they dampened DC-TNF–driven T helper (Th) type 2 cell proliferation and cytokine (IL-4, -5, and -13) secretion. They also drove the development from atopic CD4⁺CD25^loFoxp3^lo cells of a population of IL-10–secreting CD25⁺Foxp3⁺LAG-3⁺CTLA-4⁺ regulatory T cells (Tregs). These Tregs suppressed stimulatory DC–induced autologous Th2 cell proliferation and cytokine secretion in a contact-dependent manner. Our data indicate that IL-10–treated human DCs induce Th2 cell allergen tolerance ex vivo by driving the differentiation of Tregs.

Key Words: asthma • tolerance • dendritic cell • regulatory T cell • IL-10

CLINICAL RELEVANCE This report details studies in which we show that human IL-10–differentiated monocyte–derived dendritic cells (DCs; DC10) express regulatory cell markers (e.g., Ig-like transcript 2, IL-10), and can block activation of autologous subject T cells by immunostimulatory DCs (DC-TNF). The DC10 induce the outgrowth from peripheral blood CD4+ T cells of individuals with asthma of a population of IL-10–expressing CD25+Foxp3+LAG-3+CTLA-4+ regulatory T cells (Tregs), which can subsequently themselves antagonize DC-TNF activation of autologous type 2 T helper cells in a contact-dependent manner. These data suggest that DCs such as these might be useful for dampening allergen-specific responses in individuals with atopy by inducing Treg responses.