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Peng Gao [] and Zhenzhong Su [] and Xuejiao Lv [] and Jie Zhang [] and []

Academic Editor: Tânia Silvia Fröde

Department of Respiratory Medicine, The Second Affiliated Hospital of Jilin University, Changchun, China, jlu.edu.cn

Received Feb 13, 2017; Accepted Mar 26, 2017

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Introduction

Interleukin- (IL-) 35 is a member of the IL-12 cytokine family [1, 2] and was first described almost two decades ago as a heterodimer formed by the subunits Epstein-Barr-induced gene 3 (EBI3) and IL-12p35. It was found in the trophoblast component of the human placenta and suggested to be an important immunoregulator already upon discovery [3]. IL-35 induces the generation of a unique class of IL-35-producing regulatory T cells (Tregs) that are distinctly different from the other transforming growth factor beta- (TGF-β-) or IL-10-induced Tregs. These cells are called IL-35-producing iTregs (iTr35 cells) [1, 4]. IL-35 secreted by iTr35 cells in turn induces the generation of even more iTr35 cells, and thus, IL-35 and iTr35 cells create a positive feedback loop together [1].

The IL-35 receptors on the cell surface can be either homodimers of IL-12Rβ2 or gp130 or a heterodimer of IL-12Rβ2:gp130 [2]. Binding of IL-35 to its receptors leads to activation of the JAK-STAT pathway, which requires the transcription factors STAT1 and STAT4 to form a unique heterodimer [2] and induces immunosuppression, IL-35 production, and conversion of naive T cells into iTr35 cells. The heterodimeric IL-12Rβ2:gp130 receptor is required for the maximal effects to be achieved [2] (Figure 1). While the gp130 subunit is widely expressed in many different cell types, the IL-12Rβ2 subunit is mainly found on activated T cells of the Th1 subtype and natural killer cells [5]. In most resting T cells, IL-12Rβ2 is almost undetectable. However, exposure to IL-2, IL-12, IL-27, interferon- (IFN-) γ, and tumor-necrosis factor (TNF) can rapidly increase the expression of IL-12Rβ2 [2]. Expression of IL-12Rβ2 has also been shown on other immune cells, such as dendritic cells [6].

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