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 CD4Foxp3 Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4Foxp3 Treg cells and induction of oral tolerance to protect against Teff cell-mediated allergic inflammation.

RESULTS

GALT-associated pDCs preferentially generate CD4Foxp3 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 CD4Foxp3 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.