Peroxisome proliferator-activated receptor γ (PPARγ) and immunoregulation:: Enhancement of regulatory T cells through PPARγ-dependent and -independent mechanisms

Peroxisome proliferator-activated receptor (PPAR)gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism. PPAR gamma ligands, used to treat human type 2 diabetes, also down-regulate most immune system cells including APCs and pathogenic T cells. These effects putatively underlie the efficacy of PPAR gamma ligands in treating animal models of autoimmunity, leading to projections of therapeutic potential in human autoimmunity. However, the relationship between PPAR gamma ligands and CD4(+)CD25(+) regulatory T cells (Tregs) has not been examined. Specifically, no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPAR gamma ligands, and there have been no investigations of the use of PPAR gamma ligands to treat autoimmunity in the absence of Tregs. We now characterize the novel relationship between ciglitazone, a thiazolidinedione class of PPAR gamma ligand, and both murine natural Tregs (nTregs) and inducible Tregs (iTregs). In vitro, ciglitazone significantly enhances generation of iTregs in a PPAR gamma-independent manner. Surprisingly, and contrary to the current paradigm, we find that, in a model of graft-vs-host disease, the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPAR gamma. Overall, our results indicate that, unlike its down-regulatory effect on other cells of the immune system, ciglitazone has an enhancing effect on both iTregs and nTregs, and this finding may have important implications for using PPAR gamma ligands in treating human autoimmune disease.