All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation

J Exp Med. 2007 Aug 6;204(8):1765-74. doi: 10.1084/jem.20070719. Epub 2007 Jul 9.


We demonstrate that all-trans retinoic acid (RA) induces FoxP3(+) adaptive T regulatory cells (A-Tregs) to acquire a gut-homing phenotype (alpha 4 beta 7(+) CC chemokine receptor 9(+)) and the capacity to home to the lamina propria of the small intestine. Under conditions that favor the differentiation of A-Tregs (transforming growth factor-beta1 and interleukin 2) in vitro, the inclusion of RA induces nearly all activated CD4(+) T cells to express FoxP3 and greatly increases the accumulation of these cells. In the absence of RA, A-Treg differentiation is abruptly impaired by proficient antigen presenting cells or through direct co-stimulation. In the presence of RA, A-Treg generation occurs even in the presence of high levels of co-stimulation, with RA attenuating co-stimulation from interfering from FoxP3 induction. The recognition that RA induces gut imprinting, together with our finding that it enhances A-Treg conversion, differentiation, and expansion, indicates that RA production in vivo may drive both the imprinting and A-Treg development in the face of overt inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B7-1 Antigen / biosynthesis
  • B7-2 Antigen / biosynthesis
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Genomic Imprinting
  • Intestine, Small / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta1 / metabolism
  • Tretinoin / physiology*


  • B7-1 Antigen
  • B7-2 Antigen
  • Transforming Growth Factor beta1
  • Tretinoin