Hepatocytes as Cytotoxic Effector Cells

The liver is increasingly recognized as an immune competent organ wherein aberrant T cell responses to dietary or autoantigens are suppressed, thereby contributing to the maintenance of peripheral immune tolerance. Furthermore, the liver is constitutively capable of trapping and retention of activated T cells, irrespective of their antigenic specificity, leading to the proposed hypothesis that it may represent a site of elimination for activated lymphocytes. The structure of the liver readily facilitates the interaction of activated lymphocytes with other cells of the liver parenchyma, including hepatocytes. Since we have recently reported that hepatocytes constitutively express both CD95 ligand (CD95L or Fas ligand) and perforin cytotoxic molecules, which are biologically active and able to induce lysis of target cells, the cytolytic capacity of hepatocytes may contribute to the downregulation and contraction of T cell responses, as well as to elimination of other cells passing through or residing in the liver. Additionally, since we have found that these cytolytic pathways may be differentially regulated in hepatocytes in response to inflammatory cytokines, including interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα), hepatocytes should be considered as cytotoxic effector cells which may modulate the development and outcome of inflammatory diseases affecting the liver.