Crosstalk between PPARγ Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model.

S Nor Effa,Norazmi Mohd Nor,Nik Yaacob

doi:10.3390/biom8040135

Abstract

Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARγ and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independent mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARγ ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes.

Highlights

Over the past two decades since the identification of naturally-occurring CD4+ CD25+ Forkhead box P3 (Foxp3)+regulatory T cells, there has been intense research in delineating the immunobiology of naturally-occurring CD4+ CD25+ Foxp3+regulatory T cells (nTreg) cells in physiological and pathological conditions [1]
Cd5 gene that is responsible for the expression of CD5 antigen on cell surface was upregulated in ciglitazone-treated nTreg cells from Non-Obese Diabetes Resistant (NOR) mice. Since both Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Foxp3 are involved in immune suppression, we investigated whether there is cross-talk between these transcription factors in nTreg cells
Our current findings demonstrated the negative regulation of PPARγ ligands in inducing Foxp3 expression in nTreg cells of Non-Obese Diabetes (NOD) and NOR mouse models

Summary

Introduction

Over the past two decades since the identification of naturally-occurring CD4+ CD25+ Foxp3+regulatory T cells (nTreg), there has been intense research in delineating the immunobiology of nTreg cells in physiological and pathological conditions [1]. Foxp is expressed in the thymus by nTreg cells [4,5] and is transiently expressed by peripheral CD4+ CD25- conventional T cells (iTreg) [5]. In pathological conditions such as Biomolecules 2018, 8, 135; doi:10.3390/biom8040135 www.mdpi.com/journal/biomolecules. The immunosuppressive role of nTreg cells prevents such destruction from occurring by establishing peripheral self-tolerance toward these auto-reactive T cells [5]. This will hinder the development of debilitating autoimmune diseases from occurring.

Results

Discussion

Conclusion