Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen.

Hyeon-Soo Park,Alfred L. M. Bothwell,Jae-Ung Lee,Hong-Jai Park,Je-Min Choi

doi:10.1038/srep28495

Hyeon-Soo Park, Alfred L. M. Bothwell + Show 3 more

Open Access

https://doi.org/10.1038/srep28495

Copy DOI

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipocyte differentiation, has recently been connected with effector T cells, though its role is still not clear. Here, we investigated the roles of PPARγ in follicular helper T (TFH) cell responses regarding gender specificity. NP-OVA immunization in female but not male CD4-PPARγKO mice induced higher proportions of TFH cells and germinal center (GC) B cells following immunization than were seen in wild type mice. Treatment with the PPARγ agonist pioglitazone significantly reduced TFH cell responses in female mice while pioglitazone and estradiol (E2) co-treatment ameliorated TFH cells and GC responses in male mice. E2 treatment significantly enhanced PPARγ expression in male T cells, while T cell activation in the estrus but not in the diestrus stage of the menstrual cycle of females was inhibited by pioglitazone, suggesting that an estrogen-sufficient environment is important for PPARγ-mediated T cell regulation. These results demonstrate gender-based differences in sensitivities of PPARγ in TFH responses. These findings suggest that appropriate function of PPARγ is required in the regulation of female GC responses and that therapeutic strategies for autoimmune diseases using PPARγ agonists need to be tailored accordingly.

Highlights

PPARγis a transcription factor and a master regulator of adipocyte differentiation[1,2,3,4,5]
We demonstrate that an estrogen-sufficient environment promotes PPARγactivity to regulate TFH responses and we suggest that PPARγis more necessary in females to regulate effector T cell responses than it is in males
The proportion and the absolute cell number of TFH cells was significantly increased in female CD4-PPARγKO mice compared with the wild-type littermate control group, while there was a significant decrease in TFH cells in the draining lymph node of male CD4-PPARγKO mice (Fig. 1B,C, Supplementary Fig. S2a)

Summary

Introduction

PPARγis a transcription factor and a master regulator of adipocyte differentiation[1,2,3,4,5]. Thiazolidinediones (TZDs) such as pioglitazone, rosiglitazone, ciglitazone, and troglitazone are synthetic ligands for PPARγ10, and have been approved for use in the treatment of type 2 diabetes mellitus[11]. These ligands effectively inhibit NF-kB function to regulate inflammation and inflammatory diseases[12]. We observed that male CD4-PPARγKO mice do not develop autoimmune phenotypes and hypothesized that there are gender-based differences in PPARγregulation of TFH cell responses. We demonstrate that an estrogen-sufficient environment promotes PPARγactivity to regulate TFH responses and we suggest that PPARγis more necessary in females to regulate effector T cell responses than it is in males

Methods

Results

Conclusion