Role of IL-12 family cytokines in human autoimmune Uveitis

National Eye Institute

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Abstract

IL-12 family cytokines are important in host immunity. Some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, while others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered: (i) Recombinant heterodimeric IL-35 (human & mouse); (i) Recombinant heterodimeric IL-27 (human & mouse); Novel recombinant IL27p28/IL12p40 heterodimeric cytokine (p28/p40); (i) Recombinant single chain mouse IL12p35; (i) Recombinant single chain mouse IL12p40; (i) Recombinant single chain mouse IL27p28; (i) Recombinant single chain mouse Ebi3; We investigated whether each of these recombinant heterodimeric or single chain cytokines can be used to treat uveitis, a CNS inflammatory disease. Thus, far we have shown that IL-35, IL-27 and IL27p28/IL12p40 are effective in ameliorating EAU while p35, Ebi3 were found to inhibit lymphocyte proliferation. We show for the first time that IL-35 induces Bregs in vivo and promotes the conversion of Bregs to a unique Breg subset that produces IL-35 (i35-Breg). Treatment of mice with IL-35 conferred protection from autoimmune uveitis and mice that lack IL-35 or are defective in IL-35-signaling developed severe uveitis because they produced less Bregs. Ex-vivo generated Bregs also suppressed uveitis by inhibiting pathogenic Th17/Th1 cells while promoting Tregs expansion. IL-35 also induced the conversion of human B-cells into Bregs, suggesting that this function of IL-35 is evolutionarily conserved between humans and mice. We further show that IL-35 induced Bregs/i35-Bregs and suppressed uveitis by activating STAT1 and STAT3 through IL-35-Receptor comprising IL-12Rβ2/IL-27Rα subunits. Our discovery that IL-35 induces conversion of both human and mouse B-cells into Bregs, allows ex-vivo production of autologous Bregs for immunotherapy and investigating the roles of Bregs/i35-Bregs in autoimmune diseases and cancer.