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

• 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
• Journal Title: Nature Medicine
• Volume: Volume 15, Number 4
• Publisher: Nature Research (part of Springer Nature) | 2009-04, Pages 401-409
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/nm.1925
• Subjects: 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.