Abstract
We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man51-BSA) substantially reduced the BSA-induced anaphylactic response. Man51-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10–GFP knock-in (tiger) mice treated with Man51-BSA. The Man51-BSA–SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4+ type 1 regulatory T (Tr1)-like cells that expressed IL-10 and interferon-γ (IFN-γ), in a SIGNR-1– and IL-10–dependent manner, but not of CD4+CD25+Foxp3+ regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar-modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs.
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Acknowledgements
We thank A. Myers and H. Rohde for technical assistance; K. Takahara (Kyoto University) for SIGNR1-transfectant cells; and the Consortium for Functional Glycomics for SIGNR1-deficient mice. This work was supported, in part, by US National Institutes of Health grants (AI052468 and AI073610).
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Y.Z. conducted experiments involving characterizing mucosal DC subsets and their regulatory role, analyzed data and wrote the manuscript; H.K. performed in vivo experiments on antigen-induced anaphylactic responses, analyzed data and wrote the manuscript; S.-C.H. conducted experiments involving binding analyses of neoglyco-antigens; R.T.L. synthesized neoglyco-antigens and wrote the manuscript; X.Y. conducted in vitro experiments characterizing T cell responses; B.P. performed flow cytometric experiments and edited the manuscript; J.F. conducted in vivo cell transfer experiments; K.Y. contributed to the design and preparation of neoglyco-antigens; Y.C.L. designed and prepared neoglyco-antigens and supervised their synthesis; S.-K.H. planned, designed, supervised and coordinated the overall research efforts.
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Zhou, Y., Kawasaki, H., Hsu, SC. et al. Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. Nat Med 16, 1128–1133 (2010). https://doi.org/10.1038/nm.2201
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DOI: https://doi.org/10.1038/nm.2201
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