Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1+ CD8 effector cells and defective T regulatory cells (BA13P.122)

Abstract

Abstract Primary biliary cirrhosis (PBC) is an enigmatic disease mediated by autoimmune destruction of cholangiocytes in hepatic bile ducts. Early immunological events in PBC are poorly understood; clinical signs of disease occur very late in the pathological process. We have used our unique murine model of PBC in dominant-negative TGF-β receptor type II transgenic mice to delineate critical early immunopathological pathways, and previously showed that dnTGFβRII CD8 T cells alone transfer biliary disease. Herein we report significantly increased numbers of hepatic terminally differentiated (KLRG1+) CD8 T cells in dnTGFβRII compared to B6; these cells are the major cytotoxic CD8 subset. Unexpectedly, the disease is not simply CD8 T cell intrinsic since mixed bone marrow chimeric mice were protected from biliary disease. Adoptive transfer studies showed that co-transfer of B6 but not dnTGFβRII Tregs prevented dnTGFβRII CD8 T cell mediated cholangitis; the protection was associated with decreased numbers of hepatic KLRG1+ CD8 T cells and with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. DnTGFβRII Treg cells were inferior in suppressing effector CD8 T cells in vitro compared to wild type B6 Tregs. In conclusion, these results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments, which has important implications for understanding the early pathogenesis of human PBC.