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

Santhakumar Manicassamy, Rajesh Ravindran, Jiusheng Deng, Herold Oluoch, Timothy L. Denning, Sudhir Pai Kasturi, Kristen M. Rosenthal, Brian D. Evavold, Bali Pulendran

Research output: Contribution to journalArticle

225 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)401-409
Number of pages9
JournalNature Medicine
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Manicassamy, S., Ravindran, R., Deng, J., Oluoch, H., Denning, T. L., Kasturi, S. P., Rosenthal, K. M., Evavold, B. D., & Pulendran, B. (2009). Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nature Medicine, 15(4), 401-409. https://doi.org/10.1038/nm.1925