Granzyme K‐deficient mice show no evidence of impaired antiviral immunity

Abstract

The biological role of granzyme K, a serine protease of cytotoxic T lymphocytes (CTL), is controversial. It has been reported to induce perforin-mediated cell death in vitro, but is also reported to be non-cytotoxic and to operate in inflammatory processes. To elucidate the biological role of this protease, we have deleted the granzyme K gene in mice (mutant allele: Gzmk; MGI:5636646). Gzmk mice are healthy, anatomically normal, fecund and show normal hematopoietic development. Gzmk mice readily recover from lymphocytic choriomeningitis virus and mouse pox Ectromelia virus infection. Ex vivo, virus-specific granzyme K-deficient CTL are indistinguishable from those of wild-type mice in apoptosis induction of target cells. These data suggest that granzyme K does not play an essential role in viral immunity or cytotoxicity. Our granzyme K knockout line completes the collection of mouse models for the human granzymes, and will further our understanding of their biological roles and relationships.

Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

“…This study shows that GzmK is abundant in burn wounds and plays a pathogenic role in inflammation, epithelialization, and remodeling. Previously, GzmK expression was reported in cytotoxic T lymphocytes, NK, and CD4 þ T cells (Joeckel et al, 2011(Joeckel et al, , 2012(Joeckel et al, , 2017Wilson et al, 2017). Our data suggest that in burn wounds, GzmK is predominantly localized to the CD68 þ monocyte/macrophage cell populations within the dermis.…”

“…Emerging evidence challenges the notion that GzmK is cytotoxic and suggests that it may actually act to promote proinflammatory cytokine release (Joeckel et al, 2011(Joeckel et al, , 2017. Although GzmK occurs at low levels in the plasma of healthy individuals, it is acutely elevated in response to viral infection (Bade et al, 2005), allergic asthma, pneumonia (Bratke et al, 2008), sepsis (Rucevic et al, 2007), and endotoxemia (Wensink et al, 2016).…”

“…Although GzmK occurs at low levels in the plasma of healthy individuals, it is acutely elevated in response to viral infection (Bade et al, 2005), allergic asthma, pneumonia (Bratke et al, 2008), sepsis (Rucevic et al, 2007), and endotoxemia (Wensink et al, 2016). Mice infected with either lymphocytic choriomeningitis (Joeckel et al, 2017) or Chikungunya virus (Wilson et al, 2017) also show increased GzmK expression in plasma-derived cytotoxic T lymphocytes and plasma, respectively. GzmK e/e mice exhibit reduced foot swelling in response to Chikungunya virus infection (Wilson et al, 2017).…”

Mechanisms of natural killer cell-mediated cellular cytotoxicity

“…Granzyme K also shows some unique function by cleaving the pre‐mRNA‐binding protein heterogeneous ribonuclear protein K . However, granzyme K‐deficient mice do not show impaired antiviral responses, suggesting that granzyme K does not play an essential role in this process …”

“…57,58 Therefore, granzyme K seems to be a "backup" granzyme for the activity of granzyme A, which is supported by the fact that granzyme A-deficient cytotoxic T cells can still mediate cell death via granzyme K. 60 Granzyme K also shows some unique function by cleaving the pre-mRNA-binding protein heterogeneous ribonuclear protein K. 61 However, granzyme K-deficient mice do not show impaired antiviral responses, suggesting that granzyme K does not play an essential role in this process. 62…”