Local control of the immune response in the liver

The physiological function of the liver - such as removal of pathogens and antigens from the blood, protein synthesis and metabolism - requires an imm une response that is adapted to these tasks and is locally regulated. Patho genic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the inducti on of tolerance rather than the induction of immunity. The liver probably n ot only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal-veno us blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanism s and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, dir ect interaction of hepatocytes with leukocytes in the blood is unlikely. Si nusoidal endothelial cells, which line the hepatic sinusoids and separate h epatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with pas senger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor-med iated endocytosis. Liver sinusoidal endothelial cells constitutively expres s all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC c lass I and class II and CD40) and can function as antigen-presenting cells for CD4(+) and CD8(+) T cells. Thus, these cells probably contribute to hep atic immune surveillance by activation of effector T cells. Antigen-specifi c T-cell activation is influenced by the local microenvironment. This micro environment is characterized by the physiological presence of bacterial con stituents such as endotoxin and by the local release of immunosuppressive m ediators such as interleukin-10, prostaglandin Fl and transforming growth f actor-beta. Different hepatic cell populations may contribute in different ways to tole rance induction in the liver. In vitro experiments revealed that naive T ce lls are activated by resident sinusoidal endothelial cells but do not diffe rentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. B esides sinusoidal endothelial cells, other cell populations of the liver, s uch as dendritic cells, Kupffer cells and perhaps also hepatocytes, may con tribute to tolerance induction by deletion of T cells through induction of apoptosis.