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The Journal of Immunology, 2000, 164: 398-403.
Copyright © 2000 by The American Association of Immunologists

Differential Contribution of Fas- and Perforin-Mediated Mechanisms to the Cell-Mediated Cytotoxic Activity of Naive and In Vivo-Primed Intestinal Intraepithelial Lymphocytes1

Nadia Corazza*, Stefan Müller*, Thomas Brunner*, David Kägi{dagger} and Christoph Mueller2,*

* Institute of Pathology, Division of Immunopathology, University of Bern, Bern, Switzerland; and {dagger} Ontario Cancer Institute/Amgen Institute, Toronto, Ontario, Canada

Intestinal intraepithelial lymphocytes (IELs) are known to exert strong constitutive cytotoxic activity. In the present study we compared the Ag-specific cytotoxic activity and the effector mechanisms involved in non-Ag-primed, naive and in in vivo-primed IELs and splenic CD8 T cells. Ex vivo isolated naive CD8{alpha}{alpha} TCR{alpha}ß IELs, CD8{alpha}ß IELs, and splenocytes from lymphocytic choriomeningitis virus (LCMV)-specific TCR transgenic mice exert Ag-specific cytotoxic activity in a long-term, but not in a short-term, cytotoxicity assay. This cytotoxic activity is mainly Fas-Fas ligand mediated and is significantly reduced in the presence of 20 µg/ml Fas-Fc{gamma}1 fusion protein. Both CD8{alpha}ß IELs and CD8{alpha}ß splenocytes isolated from LCMV-infected C57BL/6 mice exert potent perforin-dependent cell-mediated cytotoxicity. CD8{alpha}{alpha} TCR{alpha}ß IELs from LCMV-infected animals, however, show only minimal Ag-specific cytotoxicity. The potent cytotoxic activity of in vivo activated CD8{alpha}ß IELs is not affected by the addition of Fas-Fc{gamma}1. Nevertheless CD8{alpha}ß IELs from LCMV-infected perforin-deficient mice exert Ag-specific cytotoxicity in a short-term cytotoxicity assay, and this cytotoxicity is almost completely blocked by the addition of Fas-Fc{gamma}1. These results demonstrate that naive CD8{alpha}ß IELs exert Ag-specific, Fas-Fas ligand-mediated, constitutive cytotoxic activity in a long-term cytotoxicity assay, whereas primed CD8{alpha}ß IELs primarily use the perforin-dependent exocytosis pathway to exert their potent cytotoxic activity. Furthermore, these results clearly illustrate the requirement for Ag-specific determination of IEL-mediated cytotoxicity, because the elevated, but variable, frequencies of memory-type T cells in this compartment may lead to ambiguous results when polyclonal activation or redirected assays are used.




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