PPARgamma drives conversion of inducible Tregs by stimulating dendritic cell production of retinoic acid (89.23)

Abstract

Abstract Regulatory T cells are critical in preventing autoimmunity, and peripherally-generated inducible regulatory T cells (iTregs) may also play an important regulatory role. Retinoic acid (RA) has been shown to enhance iTreg generation, and specific subsets of gastrointestinal (GI) dendritic cells (DCs) enhance iTreg generation through production of RA. The factors that regulate DC secretion of RA are unknown. We postulated that the nuclear hormone receptor PPARγ may regulate murine DC production of RA and DC-mediated generation of iTregs. PPARγ ligands are expressed in the GI tract and both down-regulate immune responses and ameliorate murine models of autoimmunity. Using splenic DCs and the synthetic PPARγ ligand Ciglitizone (Cig), we show that PPARγ activation in vitro increases iTreg generation. This increase can be blocked by LE 540, an RA inhibitor, or Citral, an RA synthesis inhibitor, and is associated with an upregulation of mRNA for RA-synthesis enzymes. In vivo administration of Cig also increases splenic DC expression of RA-synthesis genes, and, ex-vivo, these DCs enhance iTreg generation. Finally, the PPARγ-inhibitor GW9662 blocks both the baseline iTreg generation and the Cig-induced increase in iTreg generation. Our results show that PPARγ activation can increase DC RA production and DC-mediated iTreg generation, suggesting a new role for PPARγ in immunoregulation (NIH: 1R56AI072533-01A1).