The Role of TGF-β in CTB-Insulin Regulated Human Dendritic Cell Tolerance
Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the contribution of TGF-β superfamily ligand proteins to CTB-INS induction of IDO biosynthesis in human monocyte-derived DCs (moDCs). Our previous studies demonstrated that CTB-INS activates the non-canonical NF-κB pathway to induce IDO1 biosynthesis in human DCs. However, experiments presented in this dissertation demonstrate that the CTB-INS fusion protein also stimulates biosynthesis of the immunoregulatory molecules TGF-β1, activin-A and integrin αvβ8 a molecule known to activate TGF-β1. In addition, CTB-INS stimulates increased levels of Smad2/3 phosphorylation in the vaccinated DCs. Further, we confirmed that CTB-INS upregulation of the TGF-β superfamily is unrelated to IDO1 biosynthesis in human moDCs. In conclusion, our experimental findings identified novel immunoregulatory functions of CTB-INS fusion protein and suggest the fusion protein may utilize previously unidentified mechanisms for the regulation of human DC activation to mediate tolerance, a significant finding for development of clinical applications in the therapy of tissue specific autoimmunity.
Biological Phenomena, Cell Phenomena, and Immunity, Medical Cell Biology, Medical Sciences, Medicine and Health Sciences, Transforming Growth Factor beta; Receptors; Transforming Growth Factor beta; Dendritic Cells -- immunology; Cholera Toxin -- Immunology; Proinsulin -- Immunology; Recombinant Fusion Proteins -- Immunology, Immunosuppressive Cytokines; Biosynthesis; Immunological Tolerance;
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