Expression of IL-37 contributes to the immunosuppressive property of human CD4+CD25+ regulatory T cells

Abstract

Interleukin-37 (IL-37) possesses the function of down-regulate systemic and local inflammation. It is unknown whether IL-37 is expressed in human regulatory T cells (Tregs) and its role in modulating the immune response of Tregs. In the present study, cell surface molecules and secretory cytokines were analyzed in order to determine the function of IL-37 in regulating inhibitory effect of human CD4+CD25+Tregs. Meanwhile, the effects of IL-37 on T cell differentiation and proliferation as co-culture of CD4+CD25+Treg/CD4+CD25−T cell were also investigated. It was showed that IL-37 was expressed in cytoplasm of CD4+CD25+Tregs, and the levels of IL-37 were gradually elevated with the enhanced activity of CD4+CD25+Tregs. Secretory cytokines such as transforming growth factor (TGF)-β and interleukin (IL)-10, and expressions of cell surface molecules, including forkhead/winged helix transcription factor p3 (FOXP3) and cytotoxic T-lymphocyte associated antigen (CTLA)-4, were significantly decreased when IL-37 gene was silenced by siRNA. Furthermore, down-regulation of IL-37 expression in human CD4+CD25+Tregs obviously promoted proliferation of co-cultured T cell and differentiation, together with observably enhancement of IL-2 formation. These results demonstrated that IL-37 might manifest as a critical protein involving in immunosuppression of human CD4+CD25+Tregs.

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

“…As we have recently shown, silencing IL-37 in human CD4 + CD25 + Tregs obviously reduced the suppressive activity of CD4 + CD25 + Tregs30. In the current study, 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.…”

IL-37 Confers Protection against Mycobacterial Infection Involving Suppressing Inflammation and Modulating T Cell Activation

“…Furthermore, we observed a Th1 expansion in the spleen of IL-37-Tg mice infected with BCG. The expression of IL-37 in CD4+ T cells was reported previously [16], therefore it’s potentially interesting to investigate its direct effect on the differentiation of Th1 cells and the precise underlying mechanism.…”

“…We found that IL-37 was highly presented in the lung at all time points examined in the transgenic mice but not the WT mice, and an elevated IL-37 abundance was observed as early as 1 week post infection (Fig 1F). Since the ROSA26 promoter drives gene expression constitutively and ubiquitously, the increased IL-37 in the lung of transgenic mice post infection could be due to increased frequencies and numbers of cells expressing IL-37 including macrophages, dendritic cells and regulatory T cells [11,16]. Overall, recognition of mycobacteria by macrophages led to the induction of IL-37, which may contribute to elevated IL-37 in BCG-infected mice and TB patients.…”

“…The expression of IL-37 in dendritic cells (DCs) was reported to inhibit adaptive immune response by promoting generation of semimature tolerogenic DCs [11]. Moreover, IL-37 expression in human CD4 + CD25 + Treg cells was demonstrated to promote the suppressive effect on T cell activation in vitro by upregulating secretory cytokines including TGF-β and IL-10, as well as expression of cell surface molecules including transcription factor Foxp3 and cytotoxic T-lymphocyte associated antigen (CTLA)-4 [16]. Here we monitored the effect of IL-37 on Treg response in the scenario of mycobacteria infection in vivo for the first time.…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…In 2007, IL-35, a member of IL-12 family, was identified in mice as an inhibitory cytokine produced by Tregs which are involved in their suppressive function [88]. Recently, it was shown that Tregs obtained from human peripheral blood produce IL-37 to cause T-cell immunosuppression [89]. Studies performed in mice point to an additional mechanism of immune modulation by Tregs, consisting in the secretion of microvesicles.…”