The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases

Abstract

Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARΓ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4(+) T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

Fig. 1.

Structure of PPARs. PPARs have a conserved domain structure consisting of a ligand-independent activation domain (AF1), DNA-binding domain (DBD), ligand-binding domain (LBD), and ligand-dependent activation domain (AF2).

Fig. 2.

Mechanism of transcriptional regulation by PPARs. PPARs heterodimerize with retinoid X receptors (RXRs) in the presence or absence of their ligands. (A) Ligand-independent inhibition of target gene transcription. PPARs bind to response elements in the absence of their ligand and recruit co-repressor complexes for transcriptional regulation. (B) Ligand-dependent activation of target gene transcription. PPARs bind to response elements in the presence of their ligand and recruit co-activator complexes for transcriptional activation. (C) Ligand-dependent inhibition of transcription factors. PPARs can inhibit other transcription factors, such as nuclear factor-kappa B (NF-κB), by direct interaction or by outcompeting them for co-activator complexes that are required for their activation.