HEPATOCYTES INDUCE FUNCTIONAL ACTIVATION OF NAIVE CD8(-LYMPHOCYTES BUT FAIL TO PROMOTE SURVIVAL() T)

Intraperitoneal peptide injection of TCR-transgenic mice or expression of antigen in hepatocytes leads to an accumulation in the liver of sp ecific apoptotic CD8(+) T cells expressing activation markers. To dete rmine whether liver cells are capable of directly activating naive CD8 (+) T cells, we have studied the ability of purified hepatocytes to ac tivate TCR-transgenic CD8(+) T cells in vitro. We show that hepatocyte s which do not express CD80 and CD86 costimulatory molecules are able to induce activation and effective proliferation of specific naive CD8 (+) T cells in the absence of exogenously added cytokines, a property only shared by professional antigen-presenting cells (APC). Specific T cell proliferation induced by hepatocytes was comparable in magnitude to that seen in response to dendritic cells and was independent of CD 4(+) T cell help or bystander professional APC co-stimulation. During the first 3 days, the same number of divisions was observed in co-cult ures of CD8(+) T cells with either hepatocytes or splenocytes. Both AP C populations induced expression of early T cell activation markers an d specific cytotoxic T lymphocyte (CTL) activity. However, in contrast to T cells activated by splenocytes, T cells activated by hepatocytes lost their cytolytic function after 3 days of cc-culture. This correl ated with death of activated T cells, suggesting that despite efficien t activation, proliferation and transient CTL function, T cells activa ted by hepatocytes did not survive. Death could be prevented by adding antigen-expressing splenocytes or exogenous IL-2 to the co-culture, i ndicating that hepatocytes are not involved in direct killing of CD8() T cells but rather fail to promote survival. Dying cells acquired a CD8(low)TCR(low)B220(+) phenotype similar to the one described for apo ptotic intrahepatic T cells, suggesting an alternative model to accoun t for the origin of these cells in the liver. The importance of these findings for the understanding of peripheral tolerance and the ability of liver grafts to be accepted is discussed.