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The Journal of Immunology, 2004, 172: 1588-1594.
Copyright © 2004 by The American Association of Immunologists

IFN-{gamma} Promotes Fas Ligand- and Perforin-Mediated Liver Cell Destruction by Cytotoxic CD8 T Cells1

Evelyn Roth and Hanspeter Pircher2

Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany

To study liver cell damage by CTL, CD8 T cells from P14 TCR transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus with either deficiency in IFN-{gamma} (P14.IFN-{gamma}°), functional Fas ligand (P14.gld), or perforin (P14.PKO) were transferred into H8 tg mice ubiquitously expressing gp33 Ag. Treatment of H8 recipient mice with agonistic anti-CD40 Abs induced vigorous expansion of the transferred P14 T cells and led to liver cell destruction determined by increase of glutamate dehydrogenase serum levels and induction of caspase-3 in hepatocytes. Liver injury was mediated by the Fas/Fas ligand (FasL) pathway and by perforin, because P14.gld and P14.PKO T cells failed to induce increased glutamate dehydrogenase levels despite strong in vivo proliferation. In addition, H8 tg mice lacking Fas were resistant to the pathogenic effect of P14 T cells. Besides FasL and perforin, IFN-{gamma} was also required for liver cell damage, because P14.IFN-{gamma}° T cells adoptively transferred into H8 mice failed to induce disease. Moreover, Fas expression on hepatocytes from H8 recipient mice was increased after transfer of wild-type compared with P14.IFN-{gamma}° T cells, and wild-type P14 T cells expressed higher levels of FasL than P14 T cells lacking IFN-{gamma}. Thus, our data suggest that IFN-{gamma} released by activated CD8 T cells upon Ag contact facilitates liver cell destruction.




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