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

Nat Med. 2009 Apr;15(4):401-9. doi: 10.1038/nm.1925. Epub 2009 Mar 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Autoimmunity / immunology*
  • Dendritic Cells / immunology*
  • Interleukin-10 / immunology
  • Interleukin-23 / immunology
  • Lectins, C-Type
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Nerve Tissue Proteins / immunology*
  • Signal Transduction
  • Spleen / immunology
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Toll-Like Receptor 2 / immunology*
  • Vitamin A / metabolism*

Substances

  • Interleukin-23
  • Lectins, C-Type
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Toll-Like Receptor 2
  • dectin 1
  • Vitamin A
  • Interleukin-10
  • Aldehyde Dehydrogenase

Grant support