title: Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.
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 (T(reg) 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 T(reg) cells and suppressed IL-23 and T helper type 17 (T(H)17) and T(H)1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented T(H)17 and T(H)1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity.
authors.affiliation: Emory Vaccine Center, and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ravindran
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Deng
authors.forename: Herold
authors.initials: H
authors.lastname: Oluoch
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Denning
authors.forename: Sudhir Pai
authors.initials: SP
authors.lastname: Kasturi
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Rosenthal
authors.forename: Brian D
authors.initials: BD
authors.lastname: Evavold
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D014801:Vitamin A / Q000378:metabolism*; D000099181:Dectin-1
chemical_list: D000444:Aldehyde Dehydrogenase; D016753:Interleukin-10; D053759:Interleukin-23; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051195:Toll-Like Receptor 2; D014801:Vitamin A; D000099181:Dectin-1