Granzyme A, a granule-associated serine proteinase of activated cytoto
xic T cells and natural killer cells, has been reported to play a crit
ical role in DNA fragmentation of target cells. To address the questio
n of the biological role of granzyme A, we have now generated a granzy
me A-deficient mouse mutant by homologous recombination, Western blot
analysis, enzyme assays and reverse transcription-PCR confirmed the ab
sence of granzyme A in activated T cells, In addition, deletion of gra
nzyme A does not alter the expression patterns of other granule compon
ents, such as granzymes B-G and perforin. Granzyme A-deficient mice ar
e healthy and show normal hematopoietic development. Most notably, the
ir in vitro- and ex vivo-derived cytotoxic T cells and natural killer
cells are indistinguishable from those of normal mice in causing membr
ane disruption, apoptosis and DNA fragmentation in target cells, Furth
ermore, granzyme A-deficient mice readily recover from both lymphocyti
c choriomeningitis virus and Listeria monocytogenes infections and era
dicate syngeneic tumors with kinetics similar to the wild-type strain,
These results demonstrate that granzyme A does not play a primary rol
e in cell-mediated cytotoxicity, as has been assumed previously.