Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis.
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.
Sutton
Vivien R
VR
Cancer Immunology Program, Research Division, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
Waterhouse
Nigel J
NJ
Browne
Kylie A
KA
Sedelies
Karin
K
Ciccone
Annette
A
Anthony
Desiree
D
Koskinen
Aulikki
A
Mullbacher
Arno
A
Trapani
Joseph A
JA
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000502:physiology*; D020789:Cathepsin C / Q000235:genetics*; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004481:Ectromelia virus / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology*; D053804:Granzymes / Q000378:metabolism*; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology
D052899:Pore Forming Cytotoxic Proteins; C510467:perforin 1, mouse; D054353:Perforin; D020789:Cathepsin C; D053804:Granzymes; C509214:Gzmb protein, mouse