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

Abstract

Analysis of perforin-deficient mice has identified the cytolytic pathway and perforin as the preeminent effector molecule in T cellmediated control of virus infections. In this paper, we show that mice lacking both granzyme A (gzmA) and granzyme B (gzmB), which are, beside perforin, key constituents 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؋gzmB double knockout mice occurred in a dose-dependent manner, despite the expression of functionally active perforin and the absence of an intrinsic defect to generate splenic cytolytic T cells. These results establish that both gzmA and gzmB are indispensable effector molecules acting in concert with perforin in granule exocytosis-mediated host defense against natural viral pathogens.

Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis

“…GzmA À / À and GzmB À / À mice each showed only marginally increased susceptibility to ectromelia in comparison with WT; however, GzmA À / À B À / À mice were highly susceptible, similar to Pfp À / À mice. 29 This demonstrates the importance of different Gzms cooperatively mediating alternative pathways to cell death. Consistent with previous reports showing modest cytotoxic activity for mGzmA, but none for its human counterpart, 10 we found that proteolytically active recombinant human GzmA (hGzmA) was very poorly cytotoxic when administered with Pfp (Supplementary Figure S7).…”

Granzyme B-induced cell death exerted by ex vivo CTL: discriminating requirements for cell death and some of its signs

“…One example being poxvirus-encoded serine protease inhibitors that can severely curtail cytolytic effector functions, most probably by inhibiting Fas-mediated and caspase-facilitated PS exposure, resulting in uncontrolled viral spread. 36 This diversity in effector function of cytolytic pathways will also be to the host's benefit in tumor elimination.…”

A quarter century of granzymes

“…[42][43][44] In vivo, grB À/À knockout mice have shown enhanced susceptibility to mouse cytomegalovirus (MCMV), ectromelia virus, reduced graft versus host disease, and a reduced ability to clear allogeneic tumors. [45][46][47][48] However, in various other models, GrB-deficient mice remain competent at viral and tumor clearance, which is likely a reflection of Gr redundancy in these animals. 49 Granzyme H. GrH was identified through screening cDNA libraries derived from cytotoxic cells.…”