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

J Exp Med. 2009 Feb 16;206(2):343-57. doi: 10.1084/jem.20080950. Epub 2009 Feb 9.


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-beta 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-beta-mediated Foxp3 induction, at-RA potently inhibits the TGF-beta-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.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Forkhead Transcription Factors / metabolism*
  • Inducible T-Cell Co-Stimulator Ligand
  • Interleukin-10 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peyer's Patches / cytology
  • Proteins / genetics
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Toll-Like Receptor 9 / metabolism
  • Transcriptional Activation / drug effects*
  • Transcriptional Activation / immunology
  • Transforming Growth Factor beta / metabolism
  • Tretinoin / immunology
  • Tretinoin / pharmacology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Proteins
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Transforming Growth Factor beta
  • Interleukin-10
  • Tretinoin