Kupffer cells form a large intravascular macrophage bed in the liver sinusoids. The differentiation history and diversity of Kupffer cells is disputed; some studies argue that they are derived from blood monocytes, whereas others support a local origin from intrahepatic precursor cells. In the present study, we used both flow cytometry and immunohistochemistry to distinguish 2 subsets of Kupffer cells that were revealed in the context both of bone marrow transplantation and of orthotopic liver transplantation. One subset was radiosensitive and rapidly replaced from hematogenous precursors, whereas the other was relatively radioresistant and long-lived. Both were phagocytic but only the former population was recruited into inflammatory foci in response to CD8 ؉ T-cell activation. We propose the name "sessile" for the radio-

The liver exhibits a distinctive form of immune privilege, termed liver tolerance, in which orthotopic liver transplantation results in systemic donor-specific T-cell tolerance, while antigens introduced either into hepatocytes or via the portal vein also cause tolerance. Here we argue that the fundamental mechanism driving liver tolerance is likely to be the continuous exposure of diverse liver cell types to endotoxin, derived from the intestinal bacteria. This exposure promotes the expression of a set of cytokines, antigen-presenting molecules, and costimulatory signals that impose T-cell inactivation, partly via effects on liver antigen-presenting cells. The evidence favors clonal deletion mechanisms and is consistent with a role for regulatory T cells but does not support either anergy or immune deviation as important factors in liver tolerance.

The transplanted liver elicits systemic tolerance, and the underlying mechanism may also account for the persistence of liver infections, such as malaria and viral hepatitis. These phenomena have led to the hypothesis that antigen presentation within the liver is abortive, leading to T cell tolerance or apoptosis. Here we test this hypothesis in an optimized orthotopic liver transplantation model. In direct contradiction to this model, the liver itself induces full CD8+ T cell activation and differentiation. The effects of microchimerism were neutralized by bone marrow transplantation in the liver donor, and the lack of liver-derived antigen-presenting cells was documented by eight-color flow cytometry and by sensitive functional assays. We conclude that local antigen presentation cannot explain liver tolerance. On the contrary, the liver may be an excellent priming site for naive CD8+ T cells.