GRANZYME A-DEFICIENT MICE RETAIN POTENT CELL-MEDIATED CYTOTOXICITY

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.