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

215 Citations (Scopus)

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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Toll-Like Receptor 2
Tretinoin
Vitamin A
Autoimmunity
Dendritic Cells
Interleukin-23
Regulatory T-Lymphocytes
Cytokines
Enzymes
Retinaldehyde
p38 Mitogen-Activated Protein Kinases
Interleukin-10
Oxidoreductases
Pathogens
Chemical activation
dectin 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. / Manicassamy, Santhakumar; Ravindran, Rajesh; Deng, Jiusheng; Oluoch, Herold; Denning, Timothy L.; Kasturi, Sudhir Pai; Rosenthal, Kristen M.; Evavold, Brian D.; Pulendran, Bali.

In: Nature Medicine, Vol. 15, No. 4, 01.04.2009, p. 401-409.

Research output: Contribution to journalArticle

Manicassamy, S, Ravindran, R, Deng, J, Oluoch, H, Denning, TL, Kasturi, SP, Rosenthal, KM, Evavold, BD & 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, vol. 15, no. 4, pp. 401-409. https://doi.org/10.1038/nm.1925
Manicassamy, Santhakumar ; Ravindran, Rajesh ; Deng, Jiusheng ; Oluoch, Herold ; Denning, Timothy L. ; Kasturi, Sudhir Pai ; Rosenthal, Kristen M. ; Evavold, Brian D. ; Pulendran, Bali. / Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. In: Nature Medicine. 2009 ; Vol. 15, No. 4. pp. 401-409.
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