A novel lineage-specific hypersensitive site is essential for position independent granzyme B expression in transgenic mice

Duggan, Brenda; Cabilio, Nora R.; Dickie, Peter; Witmer, Jennifer; Goping, Ing Swie; Underhill, D. Alan; Bleackley, R. Chris

doi:10.1016/j.bbrc.2008.01.065

Cited by 2 publications

(4 citation statements)

References 19 publications

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“…Interestingly, the kinetics of granzyme C expression in GzmB −/− cre CTLs was identical to that of granzyme B expression in WT CTLs (true for both CD3/CD28-mediated T cell activation and IL-15-stimulated NK cell activation). Since the only difference between WT and GzmB −/− cre mice is the presence or absence of the 350-bp Avr II fragment (and the retained loxp site), we hypothesize that deletion of this fragment causes a recently defined locus control region (LCR) to “skip” granzyme B and proceed to activate the next gene downstream, granzyme C; this gene must contain regulatory elements that permit the LCR to activate it (35). Although we have demonstrated that levels of granzyme C protein expression are regulated by mRNA abundance, it remains unclear whether regulation of transcriptional activity or mRNA half-life account for the differential expression of granzyme C mRNA in WT and GzmB −/− cre lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Bleackley and colleagues (35) have recently developed strong evidence for a LCR that regulates gene expression in the granzyme B gene cluster. These investigators identified a DNA element located upstream from granzyme B that is involved in the control of its transcription (35).…”

Section: Discussionmentioning

confidence: 99%

“…These investigators identified a DNA element located upstream from granzyme B that is involved in the control of its transcription (35). In their studies, a DNase I-hypersensitive site (HS2) was detected 3.9 kb upstream from the transcriptional start site of granzyme B in activated T cells.…”

Section: Discussionmentioning

confidence: 99%

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Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes

Cai¹,

Fehniger²,

Cao³

et al. 2009

The Journal of Immunology

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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 CD8␣␣؉ 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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes

Cai¹,

Fehniger²,

Cao³

et al. 2009

The Journal of Immunology

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“…This could for instance be achieved through expression of fluorescent fusions to lytic molecules, such as Granzyme B (157) in CTL. What are the interesting questions on CTL-mediated cytotoxicity of tumor cells in vivo , besides the dynamics of the process and its general relevance for tumor elimination?…”

Section: Ctl Function During Interactions With Tumor Cells In Vivomentioning

confidence: 99%

Intravital imaging of CD8+ T cell function in cancer

Mempel

Bauer

2008

Clin Exp Metastasis

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Recent technological advances in photonics are making intravital microscopy (IVM) an increasingly powerful approach for the mechanistic exploration of biological processes in the physiological context of complex native tissue environments. Direct, dynamic and multiparametric visualization of immune cell behavior in living animals at cellular and subcellular resolution has already proved its utility in auditing basic immunological concepts established through conventional approaches and has also generated new hypotheses that can conversely be complemented and refined by traditional experimental methods. The insight that outgrowing tumors must not necessarily have evaded recognition by the adaptive immune system, but can escape rejection by actively inducing a state of immunological tolerance calls for a detailed investigation of the cellular and molecular mechanisms by which the anti-cancer response is subverted. Along with molecular imaging techniques that provide dynamic information at the population level, IVM can be expected to make a critical contribution to this effort by allowing the observation of immune cell behavior in vivo at single cell-resolution. We review here how IVM-based investigation can help to clarify the role of cytotoxic T lymphocytes (CTL) in the immune response against cancer and identify the ways by which their function might be impaired through tolerogenic mechanisms.

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A novel lineage-specific hypersensitive site is essential for position independent granzyme B expression in transgenic mice

Cited by 2 publications

References 19 publications

Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes

Differential Expression of Granzyme B and C in Murine Cytotoxic Lymphocytes

Intravital imaging of CD8+ T cell function in cancer

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