The IL-12 family cytokines have emerged as an important group of cytokines that regulate many critical aspects of host immunity, including antigen presentation, T cell lineage commitment and cytokine signaling. IL-12 family cytokines are comprised of heterodimeric protein subunits. Unique combinations of subunits can form through covalent and non-covalent binding and these include IL-12 (IL12p40 & IL12p35), IL-23 (IL12p40 and IL23p19), IL-27 (IL27p28 & EBI3 and a novel pairing between IL12p35 and EBI3 now constitutes the newly described member, IL-35. Individual subunits (e.g. IL27p28) have also been shown to have intrinsic biological activities. Our research goal has been to generate various combinations of IL-12 cytokine family subunit chains as basis for a new class of therapeutic cytokines. In this regard we have genetically engineered novel IL-12-like cytokines by pairing IL12p40 to IL27p28 and EBI3 to IL23p19 and are now defining their potential biological activities on lymphocytes and ocular cells. Specifically, we intend to use these reagents to test each subunit and various subunit combination in T cell assays to determine if they exhibit any useful biological activities and eventually, to explore their use in treating ocular diseases. 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.
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