Retinoic acid promotes the development of Arg1-expressing dendritic cells for the regulation of T-cell differentiation

Eur J Immunol. 2013 Apr;43(4):967-78. doi: 10.1002/eji.201242772. Epub 2013 Feb 14.

Abstract

Arginase I (Arg1), an enzyme expressed by many cell types including myeloid cells, can regulate immune responses. Expression of Arg1 in myeloid cells is regulated by a number of cytokines and tissue factors that influence cell development and activation. Retinoic acid, produced from vitamin A, regulates the homing and differentiation of lymphocytes and plays important roles in the regulation of immunity and immune tolerance. We report here that optimal expression of Arg1 in DCs requires retinoic acid. Induction of Arg1 by retinoic acid is directly mediated by retinoic acid-responsive elements in the 5' noncoding region of the Arg1 gene. Arg1, produced by DCs in response to retinoic acid, promotes the generation of FoxP3(+) regulatory T (Treg) cells. Importantly, blocking the retinoic acid receptor makes DCs hypo-responsive to known inducers of Arg1 such as IL-4 and GM-CSF in Arg1 expression. We found that intestinal CD103(+) DCs that are known to produce retinoic acid highly express Arg1. Our results establish retinoic acid as a key signal in expression of Arg1 in DCs.

Publication types

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

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism*
  • Binding Sites
  • Cell Differentiation / immunology*
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation / drug effects
  • Interleukin-4 / pharmacology
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Receptors, Retinoic Acid / metabolism
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Tretinoin / pharmacology*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Retinoic Acid
  • Interleukin-4
  • Tretinoin
  • Arg1 protein, mouse
  • Arginase