Specific Inhibition of Soluble γc Receptor Attenuates Collagen-Induced Arthritis by Modulating the Inflammatory T Cell Responses.

Byunghyuk Lee,Dong Hyun Sohn,Kiseok Kim,Yuna Jo,Seung-Geun Lee,Sung Ho Ryu,Euisu Shin,Laraib Amir Ali,Geona Kim,Changwan Hong

doi:10.3389/fimmu.2019.00209

Abstract

IL-17 produced by Th17 cells has been implicated in the pathogenesis of rheumatoid arthritis (RA). It is important to prevent the differentiation of Th17 cells in RA. Homodimeric soluble γc (sγc) impairs IL-2 signaling and enhances Th17 differentiation. Thus, we aimed to block the functions of sγc by inhibiting the formation of homodimeric sγc. The homodimeric form of sγc was strikingly disturbed by sγc-binding DNA aptamer. Moreover, the aptamer effectively inhibited Th17 cell differentiation and restored IL-2 and IL-15 signaling impaired by sγc with evidences of increased survival of T cells. sγc was highly expressed in SF of RA patients and increased in established CIA mice. The therapeutic effect of PEG-aptamer was tested in CIA model and its treatment alleviated arthritis pathogenesis with impaired differentiation of pathogenic Th17, NKT1, and NKT17 cells in inflamed joint. Homodimeric sγc has pathogenic roles to exacerbate RA progression with differentiation of local Th17, NKT1, and NKT17 cells. Therefore, sγc is suggested as target of a therapeutic strategy for RA.

Highlights

The common gamma chain is a cytokine receptor subunit that is shared by the γc family cytokines and is composed of IL-2,−4,−7,−9,−15, and−21 [1]
We investigated the mechanism of generating homodimeric sγc and the physiological roles of sγc in autoimmune disease, especially in rheumatoid arthritis (RA)
Since IL-17 is involved in the pathogenesis of RA [39], we expected that sγc would certainly play a role in autoimmune arthritis

Summary

Introduction

The common gamma chain (γc) is a cytokine receptor subunit that is shared by the γc family cytokines and is composed of IL-2,−4,−7,−9,−15, and−21 [1]. It has been described that the signals of γc cytokines are essential to the proliferation, differentiation, homeostasis, and activities of cells in the innate and adaptive immune systems [2, 3], showing that the genetic mutations or deficiencies of γc result in fetal immunodeficiency disorder in human and mice [4, 5]. A soluble form of γc (sγc) has recently been reported, showing that sγc is generated by alternative splicing and plays an antagonistic role in γc cytokine signaling [6]. The secreted sγc forms a homodimeric structure that binds to IL-2Rβ with a higher affinity than the monomer sγc [6]. IL-2 has important roles in controlling the balance between helper T 17 (Th17) cells and regulatory T (Treg) cells.

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