Elimination of virus-specific cytotoxic T cells in the liver

Immune responses in the liver have been studied for more than three decades, raising intriguing questions but providing few definitive answers. Many observations pertaining to immunity in this organ are unexpected and some of them even contradictory: parenchymal cells in the liver are readily accessible to circulating lymphocytes and may function as antigen-presenting cells (APC), yet antigens expressed in the liver often fail to induce responses and may cause systemic tolerance. There are rare lymphocyte classes in the liver, yet reasons why these cells reside in this organ and why immune responses are often poor remain to be elucidated. Here one of the central questions in immune responses in the liver is discussed (i.e., the ability of the adaptive T-cell-mediated immune response to clear a virus infection). An attempt is made to explain the intriguing observation that non-self-antigens expressed in the liver may induce unresponsiveness. It is shown that cell-mediated immunity to a viral infection is terminated, coincident with cell death of virus-specific cytotoxic T-lymphocytes (CTL) early after infection. Death of CTL is shown to involve interaction of Fas with Fas ligand, pointing to fratricide between activated CTL. The observation that T-cell death is inhibitable by injection of interleuken-2 is interpreted to point to a mechanism involving insufficient stimulation of T cells in conjunction with a death signal by Fas. The hypothesis is put forward that antigen presentation by unconventional APC in the liver leads to T-cell activation, in turn inducing lytic activity and expression of Fas and FasL on CTL. CTL then commit fratricide, aided by insufficient cytokine production and resulting in clonal elimination of virus-specific T cells and induction of tolerance.