Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes

Analysis of perforin-deficient mice has identified the cytolytic pathway an d perforin as the preeminent effector molecule in T cell-mediated control o f virus infections. In this paper, we show that mice lacking both granzyme A (gzmA) and granzyme B (gzmB), which are, beside perforin, key constituent s of cytolytic vesicles, are as incapable as are perforin-deficient mice of controlling primary infections by the natural mouse pathogen ectromelia, a poxvirus. Death of gzmA x gzmB double knockout mice occurred in a dose-dep endent manner, despite the expression of functionally active perforin and t he absence of an intrinsic defect to generate splenic cytolytic T cells. Th ese results establish that both gzmA and gzmB are indispensable effector mo lecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens.