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

• Published in: Nature medicine Vol. 15; no. 4; pp. 401 - 409
• Main Authors: Pulendran, Bali, Manicassamy, Santhakumar, Ravindran, Rajesh, Deng, Jiusheng, Oluoch, Herold, Denning, Timothy L, Kasturi, Sudhir Pai, Rosenthal, Kristen M, Evavold, Brian D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2009; Nature Publishing Group
• Subjects: Acids; Aldehyde Dehydrogenase - metabolism; Animals; Autoimmunity; Autoimmunity - immunology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cellular control mechanisms; Control; Dehydrogenase; Dendritic cells; Dendritic Cells - immunology; Enzymes; Immune response; Immunology; Infectious Diseases; Interleukin-10 - immunology; Interleukin-23 - immunology; Kinases; Lectins, C-Type; Membrane Proteins - immunology; Metabolic Diseases; Mice; Mice, Inbred BALB C; Molecular Medicine; Nerve Tissue Proteins - immunology; Neurosciences; Pathogens; Physiological aspects; Signal Transduction; Spleen - immunology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - immunology; Toll-Like Receptor 2 - immunology; Vitamin A; Vitamin A - metabolism
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1925

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 (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.