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Toll-like receptor 2–dependent induction of vitamin A–metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity

Nature Medicine volume 15, pages 401–409 (2009)Cite this article

Abstract

Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid metabolizing enzyme retinaldehyde dehydrogenase type 2 and interleukin-10 (IL-10) and to metabolize vitamin A and stimulate Foxp3+ T regulatory cells (Treg cells). Retinoic acid acted on DCs to induce suppressor of cytokine signaling-3 expression, which suppressed activation of p38 mitogen-activated protein kinase and proinflammatory cytokines. Consistent with this finding, TLR2 signaling induced Treg cells and suppressed IL-23 and T helper type 17 (TH17) and TH1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented TH17 and TH1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity.

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Figure 1: Mechanism of induction of vitamin-A metabolizing enzymes in splenic DCs.
Figure 2: Retinoic acid and IL-10 work synergistically to induce Foxp3+ Treg cells.
Figure 3: Retinoic acid and IL-10 exert autocrine effects on DCs to induce Socs3, which regulates activation of p38 MAPK and pro-inflammatory cytokines.
Figure 4: Induction of antigen-specific IL-10+ TR1 and Treg cells in vivo.
Figure 5: Zymosan suppresses IL-23 and TH17–mediated EAE.
Figure 6: Mechanism of induction of Raldh2 in DCs.

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Acknowledgements

We thank S. Aguilar Mertens and L. Bonner for assistance with cell sorting; D. Levesque for assistance with animal husbandry; S. Akira (Research Institute for Microbial Diseases, Osaka University) for supplying Tlr2−/− mice; G. Brown (University of Cape Town) for dectin-1–deficient mice; and G. Landreth (Case Western Reserve University) for Erk1-deficient mice. This work was supported by funding from the US National Institutes of Health (grants R01 DK057665, R01 AI048638, U19 AI057266, U54 AI057157, N01 AI50019 and N01 AI50025) and from the Bill & Melinda Gates Foundation to B.P.

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Authors and Affiliations

  1. Emory Vaccine Center, and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, 30329, Georgia, USA

    Santhakumar Manicassamy, Rajesh Ravindran, Jiusheng Deng, Herold Oluoch, Timothy L Denning, Sudhir Pai Kasturi & Bali Pulendran

  2. Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, 30322, Georgia, USA

    Kristen M Rosenthal & Brian D Evavold

  3. Department of Pathology, Emory University, 1364 Clifton Road NE, Atlanta, 30322, Georgia, USA

    Bali Pulendran

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Contributions

S.M. performed the experiments in the study, prepared the figures and helped write the paper. R.R. assisted S.M. with some of the experiments. J.D. performed some of the initial experiments. H.O. performed the immunohistology analysis. T.L.D. provided discussion and advice on some parts of the study. S.P.K. encapsulated disulphiram in microparticles. K.M.R. and B.D.E. assisted with the EAE experiments. B.P. conceived and supervised the study and, with S.M., wrote the paper.

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Correspondence to Bali Pulendran.

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Manicassamy, S., Ravindran, R., Deng, J. et al. Toll-like receptor 2–dependent induction of vitamin A–metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat Med 15, 401–409 (2009). https://doi.org/10.1038/nm.1925

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