Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells

Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Tregs) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+ T cells from dnTGFbetaRII mice to Rag1-/- recipients. We thence used this robust established adoptive transfer system and co-transferred CD8+ T cells from dnTGFbetaRII mice with either C57BL/6 or dnTGFbetaRII Foxp3+ T cells. Recipient mice were monitored for histology including portal inflammation and intra-lobular biliary cell damage and also included a study of the phenotypic changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Tregs from C57BL/6 but not dnTGFbetaRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as downregulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Tregs versus dnTGFbetaRII Tregs on the ability to downregulate autoimmune cholangitis, we noted significant differential expression of GARP, CD73, CD101, and CD103 and a functionally significant increase in IL-10 in Tregs from C57BL/6 compared to dnTGFbetaRII mice. Our data reflect the therapeutic potential of wild type CD4+ Foxp3+ Tregs in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC.