Increased Numbers of Granzyme-B-Expressing Cytotoxic T-Lymphocytes in the Small Intestine of HIV-Infected Patients

1996 ◽  
Vol 12 (3) ◽  
pp. 276-281 ◽  
Author(s):  
Fransje Snijders ◽  
Peter C. Wever ◽  
Sven A. Danner ◽  
C. Erik Hack ◽  
Fiebo J. W. ten Kate ◽  
...  
Keyword(s):  
Small Intestine ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
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.

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 The Suppressed Induction of Human Mature Cytotoxic T Lymphocytes Caused by Asbestos Is Not due to Interleukin-2 Insufficiency

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Naoko Kumagai-Takei ◽  
Yasumitsu Nishimura ◽  
Hidenori Matsuzaki ◽  
Suni Lee ◽  
Kei Yoshitome ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Mixed Lymphocyte Reaction ◽  
Asbestos Exposure ◽  
Granzyme B ◽  
Interleukin 2 ◽  
Asbestos Fibers ◽  
T Lymphocyte Proliferation ◽  
Membrane Bound ◽  
Treated Culture

We previously reported that exposure to chrysotile B (CB) asbestos suppressed the induction of mature cytotoxic T lymphocytes (CTLs) during mixed lymphocyte reaction assays (MLRs) with a decrease in the proliferation of immature CTLs. However, the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs remains unclear. Since interleukin-2 (IL-2) is a regulator of T lymphocyte proliferation, we examined the effect of IL-2 addition on suppressed CTL differentiation in CB-exposed cultures using flow cytometry (FCM). When IL-2 was added at 1 ng/mL on the second day of MLRs, the asbestos-caused decreases in the proliferation and percentages of CD25+and CD45RO+cells in CD8+lymphocytes were not recovered by IL-2 addition, although the decrease in percentage of granzyme B+cells was partially recovered. CD8+lymphocytes from the IL-2-treated culture with asbestos showed the same degree of cytotoxicity as those in cultures without IL-2 or asbestos. These findings indicate that IL-2 insufficiency is not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest a potential for the improvement of such suppressed CTL functions. Secretory factors other than IL-2 in addition to membrane-bound stimulatory molecules may play a role in asbestos-caused suppressed CTL differentiation.

scholarly journals Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes

Virology ◽  
2005 ◽  
Vol 332 (1) ◽  
pp. 16-19 ◽  
Author(s):  
Otto O. Yang ◽  
Holly Lin ◽  
Mirabelle Dagarag ◽  
Hwee L. Ng ◽  
Rita B. Effros ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Granzyme B ◽  
Hiv 1

scholarly journals G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes

2022 ◽  
Vol 10 (1) ◽  
pp. e003543
Author(s):  
Chunwan Lu ◽  
Dafeng Yang ◽  
John D Klement ◽  
Yolonda L Colson ◽  
Nicholas H Oberlies ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Immune Evasion ◽  
Aerobic Glycolysis ◽  
Granzyme B ◽  
Pentose Phosphate ◽  
Expression Level ◽  
Tumor Immune Evasion ◽  
Specific Ctls ◽  
Tumor Bearing

BackgroundGranzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate Gzmb expression in CTLs is incompletely understood.MethodsA tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion. A link between granzyme B expression and patient survival was analyzed in human patients with epithelioid mesothelioma.ResultsMesothelioma cells alone are sufficient to activate tumor-specific CTLs and to enhance aerobic glycolysis to induce a PD-1hi Gzmblo CTL phenotype. However, inhibition of lactate dehydrogenase A, the key enzyme of the aerobic glycolysis pathway, has no significant effect on tumor-induced CTL activation. Tumor cells induce H3K9me3 deposition at the promoter of G6pd, the gene that encodes the rate-limiting enzyme G6PD in the pentose phosphate pathway, to downregulate G6pd expression in tumor-specific CTLs. G6PD activation increases acetyl-coenzyme A (CoA) production to increase H3K9ac deposition at the Gzmb promoter and to increase Gzmb expression in tumor-specific CTLs converting them from a Gzmblo to a Gzmbhi phenotype, thus increasing CTL tumor lytic activity. Activation of G6PD increases Gzmb+ tumor-specific CTLs and suppresses tumor growth in tumor-bearing mice. Consistent with these findings, GZMB expression level was found to correlate with increased survival in patients with epithelioid mesothelioma.ConclusionG6PD is a metabolic checkpoint in tumor-activated CTLs. The H3K9me3/G6PD/acetyl-CoA/H3K9ac/Gzmb pathway is particularly important in CTL activation and immune evasion in epithelioid mesothelioma.

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