Critical role of plasmacytoid dendritic cells in induction of oral tolerance

Publication date: Available online 21 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Tomofumi Uto, Hideaki Takagi, Tomohiro Fukaya, Junta Nasu, Takehito Fukui, Noriaki Miyanaga, Keiichi Arimura, Takeshi Nakamura, Narantsog Choijookhuu, Yoshitaka Hishikawa, Katsuaki Sato
BackgroundExposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell–mediated immunity. Although oral tolerance is an active process that involves emergence of CD4⁺ forkhead box p3 (Foxp3)⁺ regulatory T (Treg) cells in gut-associated lymphoid tissues (GALTs) for suppression of effector T (Teff) cells, how antigen-presenting cells initiate this process remains unclear.ObjectiveWe sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance.MethodsGALT-associated pDCs in wild-type mice were examined for their ability to induce differentiation of CD4⁺ Teff cells and CD4⁺Foxp3⁺ Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4⁺Foxp3⁺ Treg cells and induction of oral tolerance to protect against Teff cell–mediated allergic inflammation.ResultsGALT-associated pDCs preferentially generate CD4⁺Foxp3⁺ Treg cells rather than CD4⁺ Teff cells, and such generation requires an autocrine loop of TGF-β for its robust production. A deficiency of pDCs abrogates antigen-specific de novo generation of CD4⁺Foxp3⁺ Treg cells occurring in GALT after antigenic feeding. Furthermore, the absence of pDCs impairs development of oral tolerance, which ameliorates the progression of delayed-type hypersensitivity and systemic anaphylaxis, as well as allergic asthma, accompanied by an enhanced antigen-specific CD4⁺ Teff cell response and antibody production.ConclusionpDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis.

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