Differential expression of granzyme B and C in murine cytotoxic lymphocytes. Journal of immunology (Baltimore, Md. : 1950) [J Immunol] Journal article | | Title | Differential expression of granzyme B and C in murine cytotoxic lymphocytes. | | Author(s) | Cai SF, Fehniger TA, Cao X, Mayer JC, Brune JD, French AR, Ley TJ | | Institution | Department of Internal Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA. | | Source | J Immunol 2009 May 15; 182(10):6287-97. | | MeSH | Animals
Antibodies, Monoclonal
CD4-Positive T-Lymphocytes
Cytomegalovirus
Cytomegalovirus Infections
Cytotoxicity, Immunologic
Flow Cytometry
Gene Expression
Granzymes
Interleukin-15
Killer Cells, Natural
Lymphocyte Culture Test, Mixed
Mice
Mice, Knockout
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes, Cytotoxic
| | 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 CD8alphaalpha(+) 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19414782 |
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