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

Abstract

Bali Pulendran and his colleagues explore ways that signaling through different pathogen receptors can program dendritic cells (DCs) to orchestrate inflammatory or tolerogenic immune responses. The yeast component zymosan triggers signaling through both Toll-like receptor 2 (TLR2) and the C-type lectin dectin-1. In the absence of TLR2, zymosan induces proinflammatory responses through dectin-1. But TLR2 triggering induces DCs to form the vitamin A–metabolizing enzyme Raldh2. The DCs can then form retinoic acid that acts in an autocrine manner on the DCs, programming them for the induction of regulatory T cell responses. 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 (Treg 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 (TH17) and TH1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented TH17 and TH1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity.