Mechanisms balancing tolerance and immunity in the liver

The liver has a pivotal role in glucose, lipid and protein metabolism as well as in removal of toxins and waste products. A unique microanatomy and a network of resident scavenger cell populations specialized in endocytic uptake of antigens and macromolecules cooperatively mediate these salient hepatic functions together with parenchymal hepatocytes. Antigens taken up by hepatic scavenger cell populations, such as Kupffer cells, hepatic dendritic cells, stellate cells and liver sinusoidal endothelial cells (LSECs), can be (cross-)presented on MHC class I and II molecules, which leads to modulation of T cell immune functions. Among these cell populations, LSECs are endowed with the highest scavenger activity and are the most efficient cell population in cross-presenting soluble exogenous antigens to CD8 T cells. Together with their large number and the high cumulative surface area, LSECs represent the hepatic cell population that is best situated to interact with circulating T cells. Under physiological conditions, antigen-specific interaction of LSECs with CD8 T cells induces tolerance that is characterized by nonresponsiveness towards T cell receptor-mediated stimulation. In contrast to functional maturation of dendritic cells by activation through pattern recognition receptors, there is no such maturation in antigen-presenting LSECs, demonstrating that even under inflammatory conditions induction of CD8 T cell tolerance is preserved. However, upon viral infection of LSECs, a unique program of T cell differentiation into effector cytotoxic T cells is initiated that is independent of currently known costimulatory signals. These results highlight specific mechanisms operative in liver-resident antigen-presenting cells governing the local balance between tolerance and immunity.