scholarly journals Granzyme-mediated Cytotoxicity Does Not Involve the Mannose 6-Phosphate Receptors on Target Cells

2004 ◽  
Vol 279 (19) ◽  
pp. 20200-20210 ◽  
Author(s):  
Ralf Dressel ◽  
Srikumar M. Raja ◽  
Stefan Höning ◽  
Tim Seidler ◽  
Christopher J. Froelich ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Knockout Mice ◽  
Granzyme B ◽  
Transformed Cells ◽  
Target Cells ◽  
Mannose 6 Phosphate ◽  
Induced Apoptosis ◽  
Dependent Pathway

Cytotoxic T lymphocytes (CTL) and natural killer cells secrete granzymes to kill infected or transformed cells. The mannose 6-phosphate receptor (Mpr) 300 on target cells has been reported to function as receptor for secreted granzyme B. Using lymphoblasts and mouse embryonal fibroblast lines from Mpr300 and Mpr46 knockout mice, we show here that both receptors are not essential for CTL-induced apoptosis. Similarly, cells exposed to either monomeric granzyme B or granzyme B-serglycin complexes readily internalize the granzyme and undergo apoptosis in the absence of Mpr300 and Mpr46. Further, no colocalization of granzyme B and Mpr300 could be observed in target cells after internalization. In conclusion, these results strongly argue against an Mpr300- or Mpr46-dependent pathway of granzyme-mediated killing and provide new insight in the internalization of monomeric and complexed granzyme B.

The granzyme B–serglycin complex from cytotoxic granules requires dynamin for endocytosis

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3845-3853 ◽  
Author(s):  
Kirstin Veugelers ◽  
Bruce Motyka ◽  
Christine Frantz ◽  
Irene Shostak ◽  
Tracy Sawchuk ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Granzyme B ◽  
Endocytic Pathway ◽  
Target Cells ◽  
Ongoing Debate ◽  
Effector Molecules ◽  
Key Factor ◽  
Dependent Pathway ◽  
Endocytic Pathways

Abstract Cytotoxic T lymphocytes and natural killer cells destroy target cells via the directed exocytosis of lytic effector molecules such as perforin and granzymes. The mechanism by which these proteins enter targets is uncertain. There is ongoing debate over whether the most important endocytic mechanism is nonspecific or is dependent on the cation-independent mannose 6-phosphate receptor. This study tested whether granzyme B endocytosis is facilitated by dynamin, a key factor in many endocytic pathways. Uptake of and killing by the purified granzyme B molecule occurred by both dynamin-dependent and -independent mechanisms. However most importantly, serglycin-bound granzyme B in high-molecular-weight degranulate material from cytotoxic T lymphocytes predominantly followed a dynamin-dependent pathway to kill target cells. Similarly, killing by live cytotoxic T lymphocytes was attenuated by a defect in the dynamin endocytic pathway, and in particular, the pathways characteristically activated by granzyme B were affected. We therefore propose a model where degranulated serglycin-bound granzymes require dynamin for uptake.

Molecular Basis of Lymphocyte-Mediated Destruction of Traget Cells

Physiology ◽  
1988 ◽  
Vol 3 (5) ◽  
pp. 211-216
Author(s):  
JD-E Young ◽  
ZA Cohn
Keyword(s):  
Natural Killer Cells ◽  
T Lymphocytes ◽  
Natural Killer ◽  
Cytotoxic T Lymphocytes ◽  
Immune Cells ◽  
Molecular Basis ◽  
Target Cells ◽  
Killer Cells

Subsets of lymphocytes, known as cytotoxic T lymphocytes or natural killer cells, are potent killers of target cells. These immune cells have large granules in their cytoplasm containing cytotoxic peptides and other factors. Several of these molecules have been isolated and their functions elucidated.

scholarly journals Estrogen Induction of the Granzyme B Inhibitor, Proteinase Inhibitor 9, Protects Cells against Apoptosis Mediated by Cytotoxic T Lymphocytes and Natural Killer Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1419-1426 ◽  
Author(s):  
Xinguo Jiang ◽  
Brent A. Orr ◽  
David M. Kranz ◽  
David J. Shapiro
Keyword(s):  
T Lymphocytes ◽  
Natural Killer ◽  
Cytotoxic T Lymphocytes ◽  
Proteinase Inhibitor ◽  
Nk Cell ◽  
Granzyme B ◽  
Liver Cells ◽  
Target Cells ◽  
Proteinase Inhibitor 9 ◽  
Estrogen Induction

Exposure to estrogens is associated with an increased risk of developing breast, cervical, and liver cancer. Estrogens strongly induce the human granzyme B inhibitor, proteinase inhibitor 9 (PI-9). Because cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the granzyme pathway to induce apoptosis of target cells, we tested the ability of activated CTLs and the human NK cell line, YT cells, to lyse human liver cells. Estrogen induction of PI-9 protected the liver cells against CTL and NK cell-mediated, granzyme-dependent, apoptosis. Knockdown of PI-9 by RNA interference blocked the protective effect of estrogen. This work demonstrates that estrogens can act on target cells to control their destruction by immune system cells and shows that induction of PI-9 expression can inhibit both CTL and NK cell-mediated apoptosis. Estrogen induction of PI-9 may reduce the ability of cytolytic lymphocytes-mediated immune surveillance to destroy newly transformed cells, possibly providing a novel mechanism for an estrogen-mediated increase in tumor incidence.

scholarly journals Granzyme B–Mediated Cytochrome C Release Is Regulated by the Bcl-2 Family Members Bid and Bax

2000 ◽  
Vol 192 (10) ◽  
pp. 1391-1402 ◽  
Author(s):  
Jeffrey A. Heibein ◽  
Ing Swie Goping ◽  
Michele Barry ◽  
Michael J. Pinkoski ◽  
Gordon C. Shore ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytochrome C ◽  
Cytotoxic T Lymphocytes ◽  
Mitochondrial Function ◽  
Granzyme B ◽  
Target Cells ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Cytolytic Granule ◽  
Independent Mechanism

Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction.

Glucocorticoid-induced apoptosis of natural killer cells and cytotoxic T lymphocytes

1992 ◽  
Vol 26 ◽  
pp. 26-27 ◽  
Author(s):  
G. Migliorati ◽  
C. Pagliacci ◽  
R. Moraca ◽  
F. Crocicchio ◽  
I. Nicoletti ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
T Lymphocytes ◽  
Natural Killer ◽  
Cytotoxic T Lymphocytes ◽  
Killer Cells ◽  
Induced Apoptosis

scholarly journals Rescue from granzyme B-induced apoptosis by Wee1 kinase.

1995 ◽  
Vol 181 (6) ◽  
pp. 2295-2300 ◽  
Author(s):  
G Chen ◽  
L Shi ◽  
D W Litchfield ◽  
A H Greenberg
Keyword(s):  
Cytotoxic T Lymphocytes ◽  
Kinase Activity ◽  
Granzyme B ◽  
Target Cells ◽  
Cyclin Dependent Kinase ◽  
Cdc2 Kinase ◽  
Transfected Cells ◽  
Wee1 Kinase ◽  
Serine Esterases ◽  
Induced Apoptosis

Granzymes are a family of granule-associated serine esterases that mediate apoptosis by cytotoxic T lymphocytes and natural killer cells. We have previously shown that cdc2, the mitosis-regulating cyclin-dependent kinase, is required for granzyme B-induced apoptosis in target cells. In addition, granzyme B induces premature activation and tyrosine dephosphorylation of cdc2 during apoptosis. Throughout most of the cell cycle and until the cell is prepared to enter mitosis, cdc2 kinase activity is negatively regulated by phosphorylation of a residue within its adenosine triphosphate-binding domain by Wee1, a nuclear kinase that maintains mitotic timing in eukaryotic cells. We have transiently expressed c-myc epitope-tagged Wee1 cDNA in BHK cells. Cells that expressed Wee1 in the nucleus became resistant to apoptosis induced by granzyme B and perforin. Wee1-transfected cells also exhibited markedly increased cdc2 tyrosine phosphorylation. Thus, Wee1 can rescue cells from granzyme-induced apoptosis by preventing cdc2 dephosphorylation.

scholarly journals HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

1978 ◽  
Vol 148 (6) ◽  
pp. 1458-1467 ◽  
Author(s):  
A McMichael
Keyword(s):  
Influenza Virus ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Human Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
The Other ◽  
Target Cells ◽  
Surface Molecules ◽  
Human Peripheral Blood Lymphocytes

Cytotoxic T lymphocytes (CTL), specific for influenza A/X31 virus, were generated from human peripheral blood lymphocytes. These CTL lysed target cells that were infected with the same virus and that shared HLA A or B locus antigens. Minimal lysis was observed when HLA-D antigens were shared. Not all HLA A and B antigens were equally effective. Efficient lysis of target cells was seen when HLA A1, A3, B7, B8, B27 and BW21 were shared with the CTL, but when HLA A2 was the only shared antigen lysis was usually minimal. This deficiency in CTL function associated with HLA A2 was not absolute. It is suggested that the function of this antigen might be influenced by other surface molecules on the cell and in particular the other HLA products.

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