Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity
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作者:
Manicassamy, Santhakumar
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Manicassamy, Santhakumar
[1
,2
]
Ravindran, Rajesh
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Ravindran, Rajesh
[1
,2
]
Deng, Jiusheng
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Deng, Jiusheng
[1
,2
]
Oluoch, Herold
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Oluoch, Herold
[1
,2
]
Denning, Timothy L.
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Denning, Timothy L.
[1
,2
]
Kasturi, Sudhir Pai
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Kasturi, Sudhir Pai
[1
,2
]
Rosenthal, Kristen M.
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Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Rosenthal, Kristen M.
[3
]
Evavold, Brian D.
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Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
Evavold, Brian D.
[3
]
Pulendran, Bali
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Emory Vaccine Ctr, Atlanta, GA 30329 USA
Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA
Emory Univ, Dept Pathol, Atlanta, GA 30322 USAEmory Vaccine Ctr, Atlanta, GA 30329 USA
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
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.