The Role of PPARGamma in the Generation and Function of Tregs

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

PPARy is a member of the nuclear hormone receptor family primarily characterized for its role in regulating glucose homeostasis. PPARy ligands, used in humans to treat type II diabetes, also significantly downregulate most cells of the immune system and have been shown to be effective in treating many murine models of autoimmune diseases. CD4+CD25+ regulatory T cells (Tregs) have been identified as playing an important role in regulating autoimmunity. Surprisingly, to date there have been no studies examining either PPARy's role in the generation or function of Tregs or the possibility that Tregs are an important target for the immunoregulatory effects of PPARy ligands. In preliminary studies, we have demonstrated a novel relationship between PPARy, PPARy ligands, and Tregs. Utilizing the PPARy ligand Ciglitazone, we first found that Ciglitazone significantly enhances the in-vitro conversion of CD4+CD25- effector T cells (Teff) to inducible Tregs (iTregs). In Specific Aim 1, we will now characterize this relationship in-vivo. We next studied the relationship between PPARy ligands and natural Tregs (nTregs). We found that ex-vivo nTregs express 10x greater levels of PPARy than ex-vivo Teff and asked whether nTregs could play a role in the in-vivo immmunotherapeutic effects of Ciglitazone. Studying the bm12 model of graft versus host disease (GVHD) we found surprisingly that nTregs were required for the immunotherapeutic effect of Ciglitazone. The goals of Specific Aim 3 are to understand this Ciglitazone-nTreg relationship and specifically to test the hypothesis that Ciglitazone enhances the function of nTregs in-vivo. (Specific Aim 2 has been eliminated in this revised proposal). Most significantly, we have generated a strain of mice in which PPARy has been specifically deleted in T cells ("T-PPAR mice"). We now document the significant utilty of these mice as research tools in our investigations, demonstrating that, in contrast to wild type nTregs, T-PPAR nTregs are incapable of mediating Ciglitazone's imunotherapeutic effect. However, even more importantly, we have found that TPPAR nTregs appear to be defective in function, even in the absence of exogenous synthetic PPARy ligands. This suggests that PPARy signaling, via endogenous ligands, plays an integral role in nTreg function. This concept will be further explored in Specific Aim 4. Overall, these studies will allow us to characterize the regulation of Tregs by exogenous PPARy ligands and study the normal role of PPARy activation in the generation and function of Tregs. This should lead to a greater understanding of Treg physiology and assist in developing strategies for immunotherapy.