The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus

•Pioglitazone selectively modulates CD4 + T cell function in SLE.•Pioglitazone induces transcriptional regulation of T cell pathways in lupus PBMCs.•Pioglitazone modulates phenotype and function of lupus regulatory T cells.•PPAR agonists should be further explored as potential therapeutic targets in SLE.

PPAR-γ agonists can suppress autoimmune responses and renal inflammation in murine lupus but the mechanisms implicated in this process remain unclear. We tested the effect of the PPAR-γ agonist pioglitazone in human lupus and control PBMCs with regard to gene regulation and various functional assays. By Affymetrix microarray analysis, several T cell-related pathways were significantly highlighted in pathway analysis in lupus PBMCs. Transcriptional network analysis showed IFN-γ as an important regulatory node, with pioglitazone treatment inducing transcriptional repression of various genes implicated in T cell responses. Confirmation of these suppressive effects was observed specifically in purified CD4 + T cells. Pioglitazone downregulated lupus CD4 + T cell effector proliferation and activation, while it significantly increased proliferation and function of lupus T regulatory cells. We conclude that PPAR-γ agonists selectively modulate CD4 + T cell function in SLE supporting the concept that pioglitazone and related,-agents should be explored as potential therapies in this disease.