Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.
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.
Manicassamy
Santhakumar
S
Emory Vaccine Center, and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA.
Ravindran
Rajesh
R
Deng
Jiusheng
J
Oluoch
Herold
H
Denning
Timothy L
TL
Kasturi
Sudhir Pai
SP
Rosenthal
Kristen M
KM
Evavold
Brian D
BD
Pulendran
Bali
B
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
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