IL27p28 inhibits induction and expression of experimental autoimmune uveitis by concurrently antagonizing autoaggressive Th1 and Th17 responses. (123.43)

Abstract

Abstract Human autoimmune uveitis is accompanied by elevated Th1 and Th17 responses. In experimental autoimmune uveitis (EAU) induced in mice with the retinal antigen IRBP, both responses are present and each effector lineage can mediate disease independently. A therapeutic approach that targets both Th1 and Th17 would therefore be attractive. IL27p28 is an antagonist of gp130, which is required for IL-6 and for IL-27 signaling. Since IL-6 and IL 27 promote Th17 and Th1 responses respectively, we hypothesized that IL27p28 would regulate EAU by affecting both responses concurrently. Overexpression of IL27p28 reduced IFN-γ and IL-17A production from eye-infiltrating CD4+ T cells and ameliorated EAU induced by active immunization. Mechanistic studies revealed that IL27p28 suppressed IL6-mediated STAT3 and IL27-mediated STAT1 phosphorylation during Th17 and Th1 polarization, respectively. Furthermore, overexpression of IL27p28 ameliorated EAU induced by passive transfer of uveitogenic effector Th1 or Th17 cells obtained from donors expressing an IRBP-specific TCR. Donor TCR-transgenic T cells recovered from these mice expressed reduced levels of Th17 and Th1 signature cytokines, IL-17A and IFN-γ, and of their corresponding transcription factors, RORγt and Tbet. The ability of IL27p28 to inhibit both Th1 and Th17 responses and to ameliorate not only the induction, but also the effector phase of EAU, bodes well for clinical usefulness of IL27p28 augmentation to control autoimmunity.