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

被引:246
作者
Manicassamy, Santhakumar [1 ,2 ]
Ravindran, Rajesh [1 ,2 ]
Deng, Jiusheng [1 ,2 ]
Oluoch, Herold [1 ,2 ]
Denning, Timothy L. [1 ,2 ]
Kasturi, Sudhir Pai [1 ,2 ]
Rosenthal, Kristen M. [3 ]
Evavold, Brian D. [3 ]
Pulendran, Bali [1 ,2 ,4 ]
机构
[1] Emory Vaccine Ctr, Atlanta, GA 30329 USA
[2] Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA
[3] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA
[4] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA
关键词
TRANS-RETINOIC ACID; ACTIVATED PROTEIN-KINASE; BETA-GLUCANS; TGF-BETA; C-FOS; DECTIN-1; DIFFERENTIATION; IMMUNITY; MACROPHAGES; GENERATION;
D O I
10.1038/nm.1925
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Foxp(3+) 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 Treg 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.
引用
收藏
页码:401 / 409
页数:9
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