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Published online February 5, 2007
doi:10.1083/jcb.200609077
The Journal of Cell Biology, Vol. 176, No. 4, 425-433
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Sutton et al.
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Article

Residual active granzyme B in cathepsin C–null lymphocytes is sufficient for perforin-dependent target cell apoptosis



Vivien R. Sutton1, Nigel J. Waterhouse1, Kylie A. Browne1, Karin Sedelies1, Annette Ciccone1, Desiree Anthony1, Aulikki Koskinen2, Arno Mullbacher2, and Joseph A. Trapani1

1 Cancer Immunology Program, Research Division, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia
2 Viral Immunology, Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia

Correspondence to Joseph A. Trapani: joe.trapani{at}petermac.org

Cathepsin C activates serine proteases expressed in hematopoietic cells by cleaving an N-terminal dipeptide from the proenzyme upon granule packaging. The lymphocytes of cathepsin C–null mice are therefore proposed to totally lack granzyme B activity and perforin-dependent cytotoxicity. Surprisingly, we show, using live cell microscopy and other methodologies, that cells targeted by allogenic CD8+ cytotoxic T lymphocyte (CTL) raised in cathepsin C–null mice die through perforin-dependent apoptosis indistinguishable from that induced by wild-type CTL. The cathepsin C–null CTL expressed reduced but still appreciable granzyme B activity, but minimal granzyme A activity. Also, in contrast to mice with inactivation of both their granzyme A/B genes, cathepsin C deficiency did not confer susceptibility to ectromelia virus infection in vivo. Overall, our results indicate that although cathepsin C clearly generates the majority of granzyme B activity, some is still generated in its absence, pointing to alternative mechanisms for granzyme B processing and activation. Cathepsin C deficiency also results in considerably milder immune deficiency than perforin or granzyme A/B deficiency.

Abbreviations used in this paper: AV, annexin V; BLT, Na-CBZ-L-lysine thiobenzyl ester; Cat, cathepsin; CTL, cytotoxic T lymphocyte; ECTV, ectromelia virus; NE, neutrophil elastase; NK, natural killer; PI, propidium iodide; PLS, Papillon-Lefevre syndrome.


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