Effects of 15-Deoxy-Δ(12,14)-Prostaglandin J2 (15d-PGJ2) and Rosiglitazone on Human Vδ2(+) T Cells

BACKGROUND: Thiazolidinediones (TZD) class of drugs, and 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) are immune regulators predicted to modulate human autoimmune disease. Their effects on γδ T cells, which are involved in animal model and human and animal autoimmune diseases, are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the activity of rosiglitazone (from the TZD class of drugs) and 15d-PGJ2 in human Vδ2 T cells. We found that 15d-PGJ2 and rosiglitazone had different effects on Vδ2 T cell functions. Both 15d-PGJ2 and rosiglitazone suppressed Vδ2 T cell proliferation in response to IPP and IL2. However, only 15d-PGJ2 suppressed functional responses including cytokine production, degranulation and cytotoxicity against tumor cells. The mechanism for 15d-PGJ2 effects on Vδ2 T cells acts through inhibiting Erk activation. In contrast, rosiglitazone did not affect Erk activation but the IL2 signaling pathway, which accounts for rosiglitazone suppression of IL2-dependent, Vδ2 T cell proliferation without affecting TCR-dependent functions. Rosiglitazone and 15d-PGJ2 are designed to be peroxisome proliferator-activated receptor gamma (PPARγ) ligands and PPARγ was expressed in Vδ2 T cell. Surprisingly, when PPARγ levels were lowered by specific siRNA, 15d-PGJ2 and rosiglitazone were still active, suggesting their target of action induces cellular proteins other than PPARγ. CONCLUSIONS/SIGNIFICANCE: The current findings expand our understanding of how the immune system is regulated by rosiglitazone and 15d-PGJ2 and will be important to evaluate these compounds as therapeutic agents in human autoimmune disease.