Modification Of Soluble Common Gamma Chain Function Controls Collagen-Induced Arthritis

Abstract IL-2Rγ (γc) is an essential subunit in γc cytokine signaling which is very important in development and homeostasis of immune cells. Recently, we showed that the soluble form of γc (sγc) is generated by alternative splicing and their production is enhanced in activated T cells. Moreover, we found that sγc inhibits γc cytokine signaling and enhances Th17 differentiation, consequently exacerbates an inflammation. Since Th17 cells are known to play pivotal roles in the pathogenesis of autoimmune rheumatoid arthritis (RA) disease, we have questioned whether sγc affects RA pathogenesis. Consistent with EAE model, we found that sγc overexpressing mice with collagen induced arthritis (CIA) displayed accelerated clinical score of arthritis compared to WT with CIA. In addition, serum level of sγc was significantly increased in CIA mice compared to WT, indicating that sγc may contribute to exacerbate the pathogenesis of RA. It is conceivable that a blockade of sγc function potentially improves autoimmune diseases. Although sγc dimerization is more functional than monomer, the dimerization mechanism of sγc is not fully understood. Using a mutant sγc form which cysteine (Cys) is replaced to alanine (Ala), we confirmed that the generation of sγc homodimer is elicited by disulfide bond. This result suggests that Cys is critical to form the dimer structure. To further study, we are designing sγc inhibitor to block sγc functions and then testing inhibitory effect in RA animal model.