Peroxisome proliferator-activated receptor α and γ agonists together with TGF-β convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells

J Immunol. 2010 Dec 15;185(12):7186-98. doi: 10.4049/jimmunol.1001437. Epub 2010 Nov 5.

Abstract

Human peripheral CD4(+)CD25(-) T cells can be induced to express Foxp3 when activated in vitro by TCR stimulation with TGF-β and IL-2. However, these TGF-β-induced Foxp3(+) regulatory T cells (iTregs) lack a regulatory phenotype. From libraries of nuclear receptor ligands and bioactive lipids, we screened three peroxisome proliferator-activated receptor (PPAR)α (bezafibrate, GW7647, and 5,8,11,14-eicosatetraynoic acid) and two PPARγ agonists (ciglitazone and 15-deoxy-Δ-(12,14)-PG J(2)) as molecules that increased Foxp3 expression in human iTregs significantly compared with that in DMSO-treated iTregs (control). These PPARα and PPARγ agonist-treated iTregs maintained a high level of Foxp3 expression and had suppressive properties. There were no significant differences in the suppressive properties of iTregs treated with the three PPARα and two PPARγ agonists, and all of the treated iTregs increased demethylation levels of the Foxp3 promoter and intronic conserved noncoding sequence 3 regions. Furthermore, PPARα and PPARγ agonists, together with TGF-β, more strongly inhibited the expression of all three DNA methyltransferases (DNMTs) (DNMT1, DNMT3a, and DNMT3b) in activated CD4(+) T cells. These results demonstrate that PPARα and PPARγ agonists together with TGF-β elicit Foxp3 DNA demethylation through potent downregulation of DNMTs and induce potent and stable Foxp3 expression, resulting in the generation of functional iTregs. Moreover, trichostatin A and retinoic acid enhanced the generation of iTregs synergistically with PPARα and PPARγ agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Methylation / drug effects
  • DNA Methylation / immunology
  • DNA Modification Methylases / biosynthesis
  • DNA Modification Methylases / immunology
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / immunology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Immunologic Factors / pharmacology*
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • PPAR alpha / agonists*
  • PPAR alpha / immunology
  • PPAR alpha / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / immunology
  • PPAR gamma / metabolism
  • Promoter Regions, Genetic / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immunologic Factors
  • PPAR alpha
  • PPAR gamma
  • Transforming Growth Factor beta
  • DNA Modification Methylases