Contrasting roles for all-trans retinoic acid in TGF-β-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells

Craig L. Maynard, Robin D. Hatton, Whitney S. Helms, James R. Oliver, Charles B. Stephensen, Casey T. Weaver

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Extrathymic induction of regulatory T (T reg) cells is essential to the regulation of effector T cell responses in the periphery. In addition to Foxp3, T reg cell expression of suppressive cytokines, such as IL-10, is essential for peripheral tolerance, particularly in the intestines. TGF-β has been shown to induce expression of Foxp3 as well as IL10 and the vitamin A metabolite; all-trans retinoic acid (RA [at-RA]) has been found to enhance the former. We report that in contrast to its enhancement of TGF-β-mediated Foxp3 induction, at-RA potently inhibits the TGF-β-mediated induction of Il10 in naive CD4 T cells. Thus, mucosal DC subsets that are active producers of at-RA inhibit induction of Il10 in naive CD4 T cells while promoting induction of Foxp3. Accordingly, mice with vitamin A deficiency have increased numbers of IL-10-competent T reg cells. Activation of DCs by certain Toll-like receptors (TLRs), particularly TLR9, suppresses T cell induction of Foxp3 and enables induction of Il10. Collectively, our data indicate that at-RA has reciprocal effects on the induction of Foxp3 and Il10 in developing CD4 + T reg cells and suggest that TLR9-dependent inhibition of at-RA production by antigen-presenting cells might represent one mechanism to promote the development of IL-10-expressing T cells.

Original languageEnglish (US)
Pages (from-to)343-357
Number of pages15
JournalJournal of Experimental Medicine
Volume206
Issue number2
DOIs
StatePublished - Feb 16 2009

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Regulatory T-Lymphocytes
Tretinoin
Interleukin-10
Genes
T-Lymphocytes
Peripheral Tolerance
Vitamin A Deficiency
Toll-Like Receptors
Antigen-Presenting Cells
Vitamin A
Intestines
Cytokines

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Contrasting roles for all-trans retinoic acid in TGF-β-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. / Maynard, Craig L.; Hatton, Robin D.; Helms, Whitney S.; Oliver, James R.; Stephensen, Charles B.; Weaver, Casey T.

In: Journal of Experimental Medicine, Vol. 206, No. 2, 16.02.2009, p. 343-357.

Research output: Contribution to journalArticle

Maynard, Craig L. ; Hatton, Robin D. ; Helms, Whitney S. ; Oliver, James R. ; Stephensen, Charles B. ; Weaver, Casey T. / Contrasting roles for all-trans retinoic acid in TGF-β-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 2. pp. 343-357.
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