Interleukin-37 Enhances the Suppressive Activity of Naturally Occurring CD4+CD25+ Regulatory T Cells.

Da-Wei Wang,Yong-Ming Yao,Xiao-Mei Zhu,Chun-Ting Wang,Yao Wu,Ning Dong

doi:10.1038/srep38955

Abstract

Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the suppression of autoimmunity and can control the immune-mediated pathology during the early phase of sepsis. Our previous data showed that silencing interleukin-37 (IL-37) in human CD4+CD25+ Tregs obviously reduced the suppressive activity of CD4+CD25+ Tregs. Here, we found that rhIL-37 stimulation markedly enhanced the suppressive activity of CD4+CD25+ Tregs isolated from naive C57BL/6 J mice in the absence or presence of lipopolysaccharide (LPS). Treatment with rhIL-37 could significantly upregulate the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4+CD25+ Tregs. Also, rhIL-37 stimulation promoted the production of transforming growth factor-β1 (TGF-β1) but not IL-10 in the supernatants of cultured CD4+CD25+ Tregs. Pretreated CD4+CD25+ Tregs with rhIL-37 in the presence or absence of LPS were cocultured with CD4+CD25− T cells, ratio of IL-4/interferon-γ in the supernatants obviously increased in IL-37-stimulated groups. In addition, early administration of IL-37 significantly improved the survival rate of septic mice induced by cecal ligation and puncture. Taken together, we concluded that rhIL-37 enhances the suppressive activity of CD4+CD25+ Tregs and might be a potential immunomodulator for the treatment of septic complications.

Highlights

There is a growing body of evidence to show that naturally occurring CD4+CD25+ regulatory T cells (Tregs) are crucial to the proper maintenance of immune self-tolerance and homeostasis[1]
CD4+CD25+ Tregs pre-treated with IL-37 in increasing concentrations for 24 hours were mixed with CD4+CD25− T cells at a ratio of 1:4
IL-37 augmented the ability of CD4+CD25+ Tregs to suppress T cells, and such response was most significant in 24-hour group (Treg D group) when stimulated with IL-37 for different time points (Fig. 1b and d)

Summary

Introduction

There is a growing body of evidence to show that naturally occurring CD4+CD25+ regulatory T cells (Tregs) are crucial to the proper maintenance of immune self-tolerance and homeostasis[1]. CD4+CD25+ Tregs constitutively express forkhead/winged helix transcription factor p3 (Foxp3), glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), and cytotoxic T-lymphocyte-associated antigen (CTLA)-4 2–4. Mice lacking these key immunoregulatory molecules will exhibit lethal lymphoproliferative phenotypes. Both human and murine CD4+CD25+ Tregs express Toll-like receptor 4 (TLR4), which can be activated by lipopolysaccharide (LPS)[5]. Tregs show a marked hypoproliferation and can obviously suppress polyclonal T cell activation in vitro by inhibiting IL-2 production[9]. The aims were to determine whether recombinant human IL-37 (rhIL-37) enhanced the suppressive activity of CD4+CD25+ Tregs in the presence or absence of LPS. The potential effects of treatment with rhIL-37 on the outcome were evaluated in mice subjected to septic challenge

Methods

Results

Conclusion