TLR2 dependent induction of vitamin A metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits TH-17 mediated autoimmunity

• Type of Material: Article
• Authors: Santhakumar Manicassamy, Emory University; Rajesh Ravindran, Emory University; Jiusheng Deng, Emory University; Herold Oluoch, Emory University; Timothy Denning, Emory University; Sudhir Kasturi, Emory University; Kristen M. Rosenthal, Emory University; Brian Evavold, Emory University; Bali Pulendran, Emory University
• Language: English
• Date: 2009-04
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Nature America, Inc. All rights reserved
• Final Published Version (URL): http://www.nature.com/nm/journal/v15/n4/full/nm.1925.html
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 15
• Issue: 4
• Start Page: 401
• End Page: 409
• Grant/Funding Information: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK; National Center for Research Resources : NCRR; National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID; Supported by funding from the U.S. National Institutes of Health (R01 DK057665, R01 AI048638, U19 AI057266, U54 AI057157, N01 AI50019, N01 AI50025), and from the Bill & Melinda Gates Foundation to B.P.
• Research Categories: Health Sciences, Immunology

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 demonstrate that the different pathogen recognition receptors, 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 (RA) metabolizing enzyme Raldh2 and IL-10, and to metabolize vitamin A and stimulate Foxp3+ T regulatory cells (Treg cells). RA acted on DCs to induce Socs3 expression, which suppressed activation of p38 MAPK and pro-inflammatory cytokines. Consistent with this, TLR2 signaling induced Treg cells, and suppressed IL-23 and TH-17/ TH-1 mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and pro-inflammatory cytokines, and augmented TH-17/ TH-1 mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of RA and immune suppression against autoimmunity.