Functional analysis of granzyme M and its role in immunity to infection.
Cytotoxic lymphocytes express a large family of granule serine proteases, including one member, granzyme (Grz)M, with a unique protease activity, restricted expression, and distinct gene locus. Although a number of Grzs, including GrzM, have been shown to mediate target cell apoptosis in the presence of perforin, the biological activity of Grz has been restricted to control of a number of viral pathogens, including two natural mouse pathogens, ectromelia, and murine CMV (MCMV). In this article, we describe the first reported gene targeting of GrzM in mice. GrzM-deficient mice display normal NK cell/T cell development and homeostasis and intact NK cell-mediated cytotoxicity of tumor targets as measured by membrane damage and DNA fragmentation. GrzM-deficient mice demonstrated increased susceptibility to MCMV infection typified by the presence of more viral inclusions and transiently higher viral burden in the visceral organs of GrzM-deficient mice compared with wild-type (WT) mice. The cytotoxicity of NK cells from MCMV-infected GrzM-deficient mice remained unchanged and, like WT control mice, GrzM-deficient mice eventually effectively cleared MCMV infection from the visceral organs. In contrast, GrzM-deficient mice were as resistant as WT control mice to mouse pox ectromelia infection, as well as challenge with a number of NK cell-sensitive tumors. These data confirm a role for GrzM in the host response to MCMV infection, but suggest that GrzM is not critical for NK cell-mediated cytotoxicity.
Pao
Lily I
LI
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Sumaria
Nital
N
Kelly
Janice M
JM
van Dommelen
Serani
S
Cretney
Erika
E
Wallace
Morgan E
ME
Anthony
Desiree A
DA
Uldrich
Adam P
AP
Godfrey
Dale I
DI
Papadimitriou
John M
JM
Mullbacher
Arno
A
Degli-Esposti
Mariapia A
MA
Smyth
Mark J
MJ
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004482:Ectromelia, Infectious / Q000276:immunology*; D053804:Granzymes; D006566:Herpesviridae Infections / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis; D007694:Killer Cells, Natural / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology; D012697:Serine Endopeptidases / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology
D053804:Granzymes; C509219:Gzmm protein, mouse; D012697:Serine Endopeptidases