Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes
Sheng F. Cai,Todd A. Fehniger,Xuefang Cao,Joshua C. Mayer,Joel D. Brune,Anthony R. French,Timothy J. Ley +6 more
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TL;DR: Granzyme C is activated with persistent antigenic stimulation, providing nonredundant backup protection for the host when granzyme B fails, and Quantitative RT-PCR revealed that granzyme C protein levels were regulated by mRNA abundance.
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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.
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TL;DR: It is shown here that granzyme B-deficient mice clear both allogeneic and syngeneic tumor cell lines more efficiently than do wild-type (WT) mice and Granzyme B and perforin are relevant for Treg cell-mediated suppression of tumor clearance in vivo.
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TL;DR: This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.
Vital involvement of a natural killer cell activation receptor in resistance to viral infection.
Michael G. Brown,Ayotunde O. Dokun,Ayotunde O. Dokun,Jonathan W. Heusel,Hamish R. C. Smith,Diana L. Beckman,Erika A. Blattenberger,Chad Dubbelde,Laurie R. Stone,Anthony A. Scalzo,Wayne M. Yokoyama +10 more
TL;DR: It is determined that the NK cell activation receptor, Ly-49H, is critically involved in resistance to murine cytomegalovirus in vivo.
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