Abstract
Granzymes (gzms) are key components of T-killer (Tc) cells believed to mediate pro-apoptotic activities. Recent evidence suggests that gzms also possess non-cytotoxic activities that contribute to host defense. In this study, we show that Tc cells from lymphocytic choriomeningitis virus (LCMV)-infected wild-type (wt) and gzm A/B-deficient mice express similar levels of gzmK protein, with both mouse strains efficiently controlling infection. GzmK, in recombinant form or secreted by ex vivo-derived LCMV-immune gzmAxB−/− Tc cells, lacks pro-apoptotic activity. Instead, gzmK induces primary mouse macrophages to process and secrete interleukin-1β, independent of the ATP receptor P2X7. Together with the finding that IL-1Ra (Anakinra) treatment inhibits virus elimination but not generation of cytotoxic Tc cells in wt mice, the data suggest that Tc cells control LCMV through non-cytotoxic processes that involve gzmK.
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Abbreviations
- gzm:
-
granzyme
- Hu:
-
human
- IL-1β:
-
interleukin-1 beta
- IL-1Ra:
-
IL-1 receptor antagonist (Anakinra)
- i.p.:
-
intraperitoneal
- ko:
-
knockout
- LCMV:
-
lymphocytic choriomeningitis virus
- MEF:
-
mouse embryonic fibroblast
- Mo:
-
mouse
- NK:
-
natural killer
- PEMØs:
-
peritoneal macrophages
- perf:
-
perforin
- p.i.:
-
post infection
- rec.:
-
recombinant
- SET:
-
nucleosome assembly protein
- SLO:
-
streptolysin O
- Tc:
-
T-killer cell
- wt:
-
wild type
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Acknowledgements
This study was supported in part by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School) and by the Centre for Biological Signaling Studies (bioss, EXC 294), both supported by the Excellence Initiative of the German Federal and State Governments, and the Deutsche Forschungsgemeinschaft (BO-1933 and GRK1104). CF was supported through 5RO1AI04494-03. JP was supported by Grant SAF2008-02139 from the Ministerio de Ciencia e Innovación (Spain) and Grant PI076/08 by Gobierno de Aragón. We thank Anton Grubisic, Aynur Ekiciler, Thomas Stehle, Bettina Hartmann, Inga Clausen, Dominik Wieland, Jüri Habicht and Christiane Brenner for their expert technical assistance. We also thank Sucharit Bhakdi for his generous gift of streptolysin O and Marina Freudenberg and Chris Galanos for providing LPS.
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Joeckel, L., Wallich, R., Martin, P. et al. Mouse granzyme K has pro-inflammatory potential. Cell Death Differ 18, 1112–1119 (2011). https://doi.org/10.1038/cdd.2011.5
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DOI: https://doi.org/10.1038/cdd.2011.5
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