T cells may respond to antigen receptor ligation by activation, functional inactivation, or the induction of apoptosis. We have examined an experimental model of peptide-driven peripheral T cell deletion, in which T cells are programmed for apoptosis following abortive activation in the periphery, but traffic to the liver in large numbers and undergo apoptosis there. We propose the hypothesis that this is a general mechanism for the destruction of T cells during antigen-driven T cell deletion, and this will be tested by using a variety of soluble and cell-associated antigens recognized by CD4+ and CD8+ T cells. The molecular mechanisms involved in homing to the liver will be identified using cell binding assays in conjunction with biochemical analysis of the cell surface. The roles of CD95 (APO-1/Fas) and its ligand will be evaluated in lpr and gld mutant mice crossed with T cell receptor transgenics. Finally, the cell biology of the interaction between activated T cells and liver parenchymal cells (hepatocytes and Kupffer cells) will be evaluated in vitro. If the hypothesis is supported, the liver will be seen to play a central role in the homeostasis of T cell number. The pathogenesis of the lpr syndrome will also be explained as a failure of CD95-mediated intrahepatic apoptosis of activated T cells. In medicine, T cell infiltration of the liver in the absence of obvious hepatocyte damage may require re- interpretation as a consequence of abortive T cell activation at other sites. Finally, the disappearance of CD4+ T cells in HIV infection may be due to enhanced apoptosis in the liver. If this is so, an understanding of the molecular mechanisms involved may lead to novel therapeutic interventions to ameliorate the effects of HIV infection on CD4+ cell numbers.
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