Cytotoxic T-Cell Response Following Mouse Liver Transplantation Is Independent of the Initial Site of T-Cell Priming

Liver transplantation in the mouse results in systemic induction of tolerance. The underlying mechanisms may also account for the persistence of chronic liver infections. It has therefore been hypothesized that antigen (Ag) presentation within the liver by nonprofessional antigen-presenting cells (APC) leads to incomplete T-cell activation, ultimately resulting in tolerance induction. We tested this hypothesis in an orthotopic mouse liver transplantation model. Mouse liver transplantation was used to manipulate antigen presentation in major histocompatibility complex (MHC)-disparate donor and recipient strains. The effect of restricted Ag presentation was studied using CD8 + T-cell receptor transgenic OT-I cells. Transgenic OT-I cells were activated by injection of their cognate peptide antigen SIINFEKL, which could be presented by the MHC class I of only one of the mouse strains. Depending on the strain combination, Ag presentation was restricted to either the transplanted liver itself, the recipient (excluding the transplanted liver), or systemically throughout the recipient. Extrahepatic Ag presentation by passenger leukocytes was eliminated by using donors of chimeric bone marrow. OT-I cells encountering antigen only in the transplanted liver were activated, underwent extensive proliferation, and developed effector functions, based on IFN-γ production and in vivo cytotoxicity assays. This T-cell activation and differentiation within the liver was comparable to animals with systemic Ag presentation and to animals with absent hepatic-parenchymal Ag presentation. The restricted presentation of antigen in the liver showed no immunosuppressive effect on activation of CD8 + T cells. In contrast, the liver may be an excellent priming site for naive CD8 + T cells.