Functional analysis of granzyme M and its role in immunity to infection

J Immunol. 2005 Sep 1;175(5):3235-43. doi: 10.4049/jimmunol.175.5.3235.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytotoxicity, Immunologic
  • Ectromelia, Infectious / immunology*
  • Granzymes
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / pathology
  • Homeostasis
  • Killer Cells, Natural / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Muromegalovirus* / immunology
  • Neoplasms, Experimental / immunology
  • Serine Endopeptidases / physiology*
  • T-Lymphocytes / physiology

Substances

  • Granzymes
  • Gzmm protein, mouse
  • Serine Endopeptidases