Abstract
BackgroundThiazolidinediones (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 FindingsWe 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/SignificanceThe 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.
Highlights
The incidence of autoimmune disease has been growing in recent years and the contribution to disease of various immune cell subsets are being defined
We report that 15d-PGJ2 and the TZD drug rosiglitazone had different effects on Vd2 T cell functions
This work will be important for understanding the effects of 15d-PGJ2 and the TZD drugs on immune responses and evaluating their application as therapeutic agents in human autoimmune disease
Summary
The incidence of autoimmune disease has been growing in recent years and the contribution to disease of various immune cell subsets are being defined. Cd T cells in mouse were reported to be an important source of IL17 [14,15,16,17,18]. These functions of activated cd T cells could contribute significantly towards inflammatory processes and promote autoimmunity. 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 cd T cells, which are involved in animal model and human and animal autoimmune diseases, are unknown
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