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

Summary 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 ( T reg ) 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 CD 8 + T cells from the dominant negative form of transforming growth factor beta receptor type II ( dnTGF‐ β RII ) mice to recombination‐activating gene ( R ag)1 –/– recipients. We then used this robust established adoptive transfer system and co‐transferred CD 8 + T cells from dnTGF‐ β RII mice with either C 57 BL /6 or dnTGF‐ β RII forkhead box protein 3 ( FoxP3 + ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of T reg from C 57 BL /6 but not dnTGF‐ β RII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down‐regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C 57 BL /6 T reg versus   dnTGF‐ β RII T reg on the ability to down‐regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GA RP ), CD 73, CD 101 and CD 103 and a functionally significant increase in interleukin ( IL )‐10 in T reg from C 57 BL /6 compared to dnTGF‐ β RII mice. Our data reflect the therapeutic potential of wild‐type CD 4 + FoxP3 + T reg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC .