The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1781/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 10, November 17, 1997 1781-1786

Brief Definitive Reports

In Vitro– and Ex Vivo–derived Cytolytic Leukocytes from Granzyme A x B Double Knockout Mice Are Defective in Granule-mediated Apoptosis but not Lysis of Target Cells

Markus M. Simon*, Michael Hausmann*, Thao Tran*, Klaus Ebnet*, Jürg Tschopp{ddagger}, Ron ThaHla§, and Arno Müllbacher§

From the * Max-Planck-Institut für Immunbiology, Stübeweg 51, D-79108 Freiburg, Germany; {ddagger} Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; and § Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra City, A.C.T. 2601, Australia

Granzyme (gzm) A and gzmB have been implicated in Fas-independent nucleolytic and cytolytic processes exerted by cytotoxic T (Tc) cells, but the underlying mechanism(s) remains unclear. In this study, we compare the potential of Tc and natural killer (NK) cells of mice deficient in both gzmA and B (gzmAxB–/–) with those from single knockout mice deficient in gzmA (–/–), gzmB (–/–), or perforin (–/–) to induce nuclear damage and lysis in target cells. With the exception of perforin–/–, all in vitro– and ex vivo–derived Tc and NK cell populations from the mutant strains induced 51Cr-release in target cells at levels and with kinetics similar to those of normal mice. This contrasts with their capacity to induce apoptotic nuclear damage in target cells. In gzmAxB–/– mice, Tc/NK-mediated target cell DNA fragmentation was not observed, even after extended incubation periods (10 h), but was normal in gzmA-deficient and only impaired in gzmB-deficient mice in short-term (2–4 h), but not long-term (4–10 h), nucleolytic assays. This suggests that gzmA and B are critical for Tc/NK granule– mediated nucleolysis, with gzmB being the main contributor, while target cell lysis is due solely to perforin and independent of both proteases.

Address correspondence to Dr. Markus M. Simon, Max-Planck-Institut für Immunbiologie, Stübeweg 51, D-79108 Freiburg, Germany. Phone: 49-761-5108-533; FAX: 49-761-5108-529; E-mail: simon{at}immunbiol.mpg.de Klaus Ebnet's present address is Institut für Zellbiologie, ZMBE, D-48149 Münster, Germany.


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