Critical role of plasmacytoid dendritic cells in induction of oral tolerance - 06/06/18
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Mucosal immunity, oral tolerance, dendritic cells, regulatory T cells, allergy
Abbreviations used : ALDH, APC, BALF, cDC, CFA, DC, DT, DTH, EGFP, Foxp3, GALT, IDO, iTreg, LP, MLN, OVA, OVAp, pDC, PGN, RA, siLP, TCR, Teff, TLR, Treg
Plan
Supported by a Grant-in-Aid for Challenging Exploratory Research (to K.S.) and for Young Scientists (B; to T.U. T.F., and H.T.) from the Ministry of Education, Science and Culture of Japan; the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and development (AMED; to K.S.); the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); the Uehara Memorial Foundation (to K.S. and H.T.); the Takeda Science Foundation (to H.T. and T.F.); the Novartis Foundation (Japan) for the Promotion of Science (to H.T.); the Kato Memorial Bioscience Foundation (to H.T.); the Nagao Memorial Fund (to H.T.); the Daiichi Sankyo Foundation of Life Science (to K.S.); the Naito Foundation (to K.S.); the GSK Japan Research Grant (to T.F. and H.T.); and Bristol-Myers Squibb Foundation Grants (to K.S.). |
|
Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 6
P. 2156 - juin 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?