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

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 gamma c (s gamma c) impairs IL-2 signaling and enhances Th17 differentiation. Thus, we aimed to block the functions of s gamma c by inhibiting the formation of homodimeric s gamma c. The homodimeric form of s gamma c was strikingly disturbed by s gamma c-binding DNA aptamer. Moreover, the aptamer effectively inhibited Th17 cell differentiation and restored IL-2 and IL-15 signaling impaired by s gamma c with evidences of increased survival of T cells. s gamma c 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 s gamma c has pathogenic roles to exacerbate RA progression with differentiation of local Th17, NKT1, and NKT17 cells. Therefore, s gamma c is suggested as target of a therapeutic strategy for RA.