Toll-like Receptor 2-dependent Induction of Vitamin A-metabolizing Enzymes in Dendritic Cells Promotes T Regulatory Responses and Inhibits Autoimmunity

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2009 Mar 3

PMID 19252500

Citations 160

Authors

Santhakumar Manicassamy

Rajesh Ravindran

Jiusheng Deng

Herold Oluoch

Timothy L Denning

Sudhir Pai Kasturi

Kristen M Rosenthal

Brian D Evavold

Bali Pulendran

Affiliations

Soon will be listed here.

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.

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