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* Division of Oncology, Departments of Internal Medicine and Genetics, Siteman Cancer Center, Washington University School of Medicine, and
Division of Hematology/Oncology, Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO 63110
Although the functions of granzyme A (GzmA) and GzmB are well-defined, a number of orphan granzymes of unknown function are also expressed in cytotoxic lymphocytes. Previously, we showed that a targeted loss-of-function mutation for GzmB was associated with reduced expression of several downstream orphan granzyme genes in the lymphokine-activated killer cell compartment. To determine whether this was caused by the retained phosphoglycerate kinase I gene promoter (PGK-neo) cassette in the GzmB gene, we retargeted the GzmB gene with a LoxP-flanked PGK-neo cassette, then removed the cassette in embryonic stem cells by transiently expressing Cre recombinase. Mice homozygous for the GzmB null mutation containing the PGK-neo cassette (GzmB–/–/+PGK-neo) displayed reduced expression of the closely linked GzmC and F genes in their MLR-derived CTLs and lymphokine-activated killer cells; removal of the PGK-neo cassette (GzmB–/–/
PGK-neo) restored the expression of both genes. Cytotoxic lymphocytes derived from mice with the retained PGK-neo cassette (GzmB–/–/+PGK-neo) had a more severe cytotoxic defect than those deficient for GzmB only (GzmB–/–/PGK-neo). Similarly, GzmB–/–/+PGK-neo mice displayed a defect in the allogeneic clearance of P815 tumor cells, whereas GzmB–/–/PGK-neo mice did not. These results suggest that the retained PGK-neo cassette in the GzmB gene causes a knockdown of GzmC and F expression, and also suggest that these granzymes are relevant for the function of cytotoxic lymphocytes in vitro and in vivo.
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