Enhanced CD25+Foxp3+ regulatory T cell development by amodiaquine through activation of nuclear receptor 4A

Hee Yeon Won,Sera Oh,Hana Jeong,Eun Sook Hwang,Ji Hyun Shin

doi:10.1038/s41598-017-17073-y

Abstract

CD4+ T cells play key roles in the regulation of immune responses against pathogenic infectious antigens via development into effector T helper and induced regulatory T (iTreg) cells. Particularly, CD4+CD25+Foxp3+ iTreg cells are crucial for maintaining immune homeostasis and controlling inflammatory diseases. Anti-inflammatory drugs that enhance iTreg cell generation would be effective at preventing and treating inflammatory and autoimmune diseases. In this study, we examined whether anti-malarial and anti-arthritic amodiaquine (AQ) could affect iTreg cell development. Despite the anti-proliferative activity of AQ, AQ only moderately decreased iTreg cell proliferation but substantially increased IL-2 production by iTreg cells. Furthermore, AQ dose-dependently increased iTreg cell development and significantly upregulated iTreg cell markers including CD25. Interestingly, CD25 expression was decreased at later stages of iTreg cell development but was sustained in the presence of AQ, which was independent of IL-2 signaling pathway. AQ directly increased CD25 gene transcription by enhancing the DNA-binding and transcriptional activity of nuclear receptor 4 A. Most importantly, in vivo administration of AQ attenuated inflammatory colitis, resulted in the increased iTreg cells and decreased inflammatory cytokines. The ability of anti-malarial AQ to potentiate iTreg cell development makes it a promising drug for preventing and treating inflammatory and autoimmune diseases.

Highlights

CD4+ T cells play crucial roles in the induction of optimal immune responses against pathogenic infections including bacteria, viruses, and malaria parasites by differentiating into effector T helper (Th) cells, such as Th1, Th2, and Th17 cells[1,2,3]
Our results indicate that AQ promotes iTreg cell development through a significant induction of CD25 and subsequently increases Foxp[3] expression, which are controlled by activation of Nuclear receptor 4A proteins (NR4As), and suppresses inflammatory colitis, induced by T cells
Our study demonstrated that AQ functioned as an activator of CD25+Foxp3+ Treg cell development through a significant induction of CD25 expression

Summary

Introduction

CD4+ T cells play crucial roles in the induction of optimal immune responses against pathogenic infections including bacteria, viruses, and malaria parasites by differentiating into effector T helper (Th) cells, such as Th1, Th2, and Th17 cells[1,2,3]. Our results indicate that AQ promotes iTreg cell development through a significant induction of CD25 and subsequently increases Foxp[3] expression, which are controlled by activation of NR4A, and suppresses inflammatory colitis, induced by T cells. AQ treatment substantially enhanced IL-2 gene transcription and IL-2-producing cell populations, as confirmed by real time-PCR and intracellular cytokine staining (Fig. 2B and C).

Results

Conclusion