Critical role of plasmacytoid dendritic cells in induction of oral tolerance

Background Exposure 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. Objective We sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance. Methods GALT-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. Results GALT-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. Conclusion pDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis.