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Article
Nature Medicine 15, 401 - 409 (2009)
Published online: 1 March 2009 | doi:10.1038/nm.1925
Toll-like receptor 2–dependent induction of vitamin A–metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity
Santhakumar Manicassamy1, Rajesh Ravindran1, Jiusheng Deng1, Herold Oluoch1, Timothy L Denning1, Sudhir Pai Kasturi1, Kristen M Rosenthal2, Brian D Evavold2 & Bali Pulendran1,3
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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