Specific Inhibition of Soluble γc 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 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.

CD4+ T-Cells With High Common γ Chain Expression and Disturbed Cytokine Production Are Enriched in Children With Type-1 Diabetes

“…T-cell sensitivity for IL-2 and IL-7 depends on IL-2Rα and IL-7Rα receptor expression levels (8). Furthermore, initial studies indicated a role of the shared γ c receptor and its soluble variant in autoimmune pathogenesis (22, 25, 27). Therefore, we performed a case-control study and identified higher γ c and IL-7Rα chain expression on CD4 + T-cells from T1D patients.…”

“…Although direct association analyses were not possible in STAT5 phosphorylation assays, we concluded that cytokine sensitivity of γ c high T-cell proportions promoted IL-2 (IL-15) rather than IL-7. Evidence for a role of differential γ c -dependent γ c cytokine signaling come from several animal models including experimental autoimmune encephalitis (EAE) and rheumatoid arthritis (25, 27, 32–34). Hong et al assessed implications of the sγ c chain on cytokine signaling and found that this inhibitory variant especially blocked IL-2R signaling probably by binding to the IL-2Rß chain and preventing the association with membrane γ c proteins (27).…”

“…Hong et al assessed implications of the sγ c chain on cytokine signaling and found that this inhibitory variant especially blocked IL-2R signaling probably by binding to the IL-2Rß chain and preventing the association with membrane γ c proteins (27). Sγ c mediated impaired IL-2 response of T cells caused increased IL-17 production and worsening of EAE and arthritis symptoms (25, 27). Here we detected a promoted IL-2 response in T1D patients with high membrane γ c expression.…”

“…Evidence for a potential role of γ c in T1D pathology comes from the study of Demirci et al who showed that antibodies against γ c prevented T1D disease onset in animal models (22). Chronic inflammatory diseases may also be affected by γ c expression since increased serum concentrations of the soluble (s)γ c variant were reported in human inflammatory bowel disease (23) and rheumatoid arthritis (24, 25).…”

The anti-inflammatory potential of cefazolin as common gamma chain cytokine inhibitor

“…IL-15•sIL-15Rα heterodimer surpasses in stability and activity the poorly secreted and unstable monomeric IL-15 [41][42][43] . Growing evidence points also to soluble γ c (sγ c ) as a contributor to the aggravation of inflammatory autoimmune diseases 44 . Therefore, both sIL-15Rα and sγ c have been suggested as therapeutic targets for inflammatory diseases.…”