Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes
Open Access
- 15 May 2009
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 182 (10), 6287-6297
- https://doi.org/10.4049/jimmunol.0804333
Abstract
Cytotoxic lymphocytes use the granule exocytosis pathway to kill pathogen-infected cells and tumor cells. Although many genes in this pathway have been extensively characterized (e.g., perforin, granzymes A and B), the role of granzyme C is less clear. We therefore developed a granzyme C-specific mAb and used flow cytometry to examine the expression of granzyme B and C in the lymphocyte compartments of wild-type and mutant GzmB−/− cre mice, which have a small deletion in the granzyme B gene. We detected granzyme B and C expression in CD4+ and CD8+ T cells activated with CD3/CD28 beads or MLRs. Stimulation of NK cells in vitro with IL-15 also induced expression of both granzymes. Granzyme C up-regulation was delayed relative to granzyme B in wild-type lymphocytes, whereas GzmB−/− cre cells expressed granzyme C earlier and more abundantly on a per-cell basis, suggesting that the deleted 350-bp region in the granzyme B gene is important for the regulation of both granzymes B and C. Quantitative RT-PCR revealed that granzyme C protein levels were regulated by mRNA abundance. In vivo, a population of wild-type CD8αα+ intraepithelial lymphocytes constitutively expressed granzyme B and GzmB−/− cre intraepithelial lymphocytes likewise expressed granzyme C. Using a model of a persistent murine CMV infection, we detected delayed expression of granzyme C in NK cells from infected hosts. Taken together, these findings suggest that granzyme C is activated with persistent antigenic stimulation, providing nonredundant backup protection for the host when granzyme B fails.Keywords
This publication has 39 references indexed in Scilit:
- Human and Mouse Granzyme A Induce a Proinflammatory Cytokine ResponseImmunity, 2008
- A novel lineage-specific hypersensitive site is essential for position independent granzyme B expression in transgenic miceBiochemical and Biophysical Research Communications, 2008
- Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell DeathAnnual Review of Immunology, 2008
- Natural killer cell–derived human granzyme H induces an alternative, caspase-independent cell-death programBlood, 2007
- Acquisition of Murine NK Cell Cytotoxicity Requires the Translation of a Pre-existing Pool of Granzyme B and Perforin mRNAsImmunity, 2007
- Rapid emergence of escape mutants following infection with murine cytomegalovirus in immunodeficient miceClinical Immunology, 2005
- Escape of Mutant Double-Stranded DNA Virus from Innate Immune ControlImmunity, 2004
- The genes for perforin, granzymes A–C and IFN‐γ are differentially expressed in single CD8+ T cells during primary activationInternational Immunology, 2002
- Lymphocyte-Mediated CytotoxicityAnnual Review of Immunology, 2002
- The Molecular Basis of AllorecognitionAnnual Review of Immunology, 1993