Both passenger leucocytes and hepatic parenchyma contribute to activation and deletion of graft-reactive CD8 T cells in liver transplantation (P2130)

Abstract Unlike most solid organs, liver transplants are spontaneously accepted across MHC mismatch and induce donor-specific tolerance. The mechanisms and site of tolerance induction remain unclear. Both recipient lymphoid tissues (RLT) where donor passenger leukocytes (PL) migrate, and the liver parenchyma itself are thought to contribute to this process by inducing abortive activation of alloreactive T cells. To determine the relative contribution of these compartments to alloreactive T cell fate, we developed a murine liver transplant model in which we traced the fate of PL and a naïve alloreactive CD8 T cell reporter population specific for donor MHC. Ly5.2+C57BL/6 livers were transplanted into allogeneic Ly5.1+B10.BR recipients. Directly allograft reactive Des-TCR transgenic T cells specific for donor H-2Kb were adoptively transferred as a reporter population. Donor and recipient leukocyte location and fate were traced by flow cytometry and radiolabelling. All Des T cells were rapidly activated in RLT and liver but numbers dropped dramatically within 48h, with cells resident in RLT predominantly dying in situ, while most circulating Des T cells were deleted in the liver. Intrahepatic clearance was associated with degradation of Des T cells in hepatocyte lysosomal compartments. In conclusion, these results show that both PL and the hepatic parenchyma contribute to deletion of graft reactive T cells, and reveal a novel mechanism of tolerance induction within the hepatic allograft.