Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2352-2355 ◽  
Author(s):  
Masaki Yasukawa ◽  
Hideki Ohminami ◽  
Junko Arai ◽  
Yoshihito Kasahara ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Hla Antigens ◽  
Peripheral Blood Lymphocytes ◽  
Messenger Rnas ◽  
Granule Exocytosis ◽  
Ligand System ◽  
Concanamycin A ◽  
Main Pathway

We investigated the cytotoxicity mechanisms of alloantigen-specific human CD4+ and CD8+ cytotoxic T lymphocytes (CTLs) using cells from family members with the Fas gene mutation. Alloantigen-specific CD4+ and CD8+ CTL bulk lines and clones were generated from 2 individuals by stimulation of their peripheral blood lymphocytes with allogeneic Fas−/− or Fas+/− cell lines that were established from B-lymphocytes of a patient with Fas deficiency and her mother, respectively. Both CD4+ and CD8+CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas−/− and Fas+/− cells to almost the same degree. The cytotoxicity of CD4+ and CD8+ CTLs appeared to be Ca2+-dependent and was completely inhibited by concanamycin A, an inhibitor of perforin-mediated cytotoxicity. Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand, perforin, and granzyme B were all detected in these CD4+CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4+ CTL clones that showed Fas-independent cytotoxicity were TH0, as determined by their cytokine production profile. These data, obtained with the use of a novel experimental system, clearly show that the main pathway of cytotoxicity mediated by alloantigen-specific human CD4+as well as by CD8+ CTLs is granule exocytosis, and not the Fas/Fas ligand system.

Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2352-2355 ◽  
Author(s):  
Masaki Yasukawa ◽  
Hideki Ohminami ◽  
Junko Arai ◽  
Yoshihito Kasahara ◽  
Yasushi Ishida ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Hla Antigens ◽  
Peripheral Blood Lymphocytes ◽  
Messenger Rnas ◽  
Granule Exocytosis ◽  
Ligand System ◽  
Concanamycin A ◽  
Main Pathway

Abstract We investigated the cytotoxicity mechanisms of alloantigen-specific human CD4+ and CD8+ cytotoxic T lymphocytes (CTLs) using cells from family members with the Fas gene mutation. Alloantigen-specific CD4+ and CD8+ CTL bulk lines and clones were generated from 2 individuals by stimulation of their peripheral blood lymphocytes with allogeneic Fas−/− or Fas+/− cell lines that were established from B-lymphocytes of a patient with Fas deficiency and her mother, respectively. Both CD4+ and CD8+CTL bulk lines and clones directed against allogeneic HLA antigens exerted cytotoxicity against Fas−/− and Fas+/− cells to almost the same degree. The cytotoxicity of CD4+ and CD8+ CTLs appeared to be Ca2+-dependent and was completely inhibited by concanamycin A, an inhibitor of perforin-mediated cytotoxicity. Messenger RNAs for the major mediators of CTL cytotoxicity, Fas ligand, perforin, and granzyme B were all detected in these CD4+CTLs with the use of the reverse transcriptase polymerase chain reaction. The majority of CD4+ CTL clones that showed Fas-independent cytotoxicity were TH0, as determined by their cytokine production profile. These data, obtained with the use of a novel experimental system, clearly show that the main pathway of cytotoxicity mediated by alloantigen-specific human CD4+as well as by CD8+ CTLs is granule exocytosis, and not the Fas/Fas ligand system.

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3853-3858 ◽  
Author(s):  
Peter Chu ◽  
William G. Wierda ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Apoptosis Pathway ◽  
Granule Exocytosis ◽  
Concanamycin A ◽  
Cd40 Activation

Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3853-3858 ◽  
Author(s):  
Peter Chu ◽  
William G. Wierda ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Apoptosis Pathway ◽  
Granule Exocytosis ◽  
Concanamycin A ◽  
Cd40 Activation

Abstract Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

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.

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

Fas-ligand-mediated lysis of erbB-2-expressing tumour cells by redirected cytotoxic T lymphocytes

1999 ◽  
Vol 47 (5) ◽  
pp. 278-286 ◽  
Author(s):  
Nicole M. Haynes ◽  
Mark J. Smyth ◽  
Michael H. Kershaw ◽  
Joseph A. Trapani ◽  
Phillip K. Darcy
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Fas Ligand ◽  
Tumour Cells

Fas-Independent and Nonapoptotic Cytotoxicity Mediated by a Human CD4+ T-Cell Clone Directed Against an Acute Myelogenous Leukemia–Associated DEK-CAN Fusion Peptide

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 925-935 ◽  
Author(s):  
Hideki Ohminami ◽  
Masaki Yasukawa ◽  
Shin Kaneko ◽  
Yoshihiro Yakushijin ◽  
Yasuhito Abe ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Fas Ligand ◽  
Cell Clone ◽  
Fusion Peptide ◽  
Peripheral Blood Lymphocytes ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Concanamycin A ◽  
T Cell Clone ◽  
Acute Myelogenous

The mechanism underlying the cytotoxicity mediated by a human CD4+ cytotoxic T-lymphocyte (CTL) clone directed against a peptide derived from the acute myelogenous leukemia-associated fusion protein, DEK-CAN, was investigated. A DEK-CAN fusion peptide-specific CD4+ Th0 CTL clone, designated HO-1, was established from the peripheral blood lymphocytes of a healthy individual. HO-1 exerted direct but not “innocent bystander” cytotoxicity within 2 hours. The cytotoxicity mediated by HO-1 was completely Ca2+-dependent. Because HO-1 lysed peptide-loaded Fas-deficient target cells derived from a patient with a homozygousFas gene mutation, its cytotoxicity appeared to be mediated by a Fas-independent pathway. In addition, its cytotoxicity was only partially inhibited by treatment with concanamycin A and strontium ions, which are inhibitors of the perforin-based cytotoxic pathway. Although membrane-bound type of tumor necrosis factor- (TNF-) was expressed on HO-1, an anti–TNF- antibody had no effect on HO-1–mediated cytotoxicity. HO-1 expressed mRNA for apoptosis-inducing mediators, including perforin, granzyme B, Fas ligand, TNF-, and lymphotoxin; however, no DNA fragmentation was detected in target cells incubated with HO-1 by 5-[125I]Iodo-2′-deoxyuridine release assay and agarose gel electrophoresis of DNA. Although it has been suggested that the Fas/Fas ligand system is the main pathway by which CD4+ CTL-mediated cytotoxicity is exerted in murine systems, HO-1 produced peptide-specific and HLA-restricted cytotoxicity via a Fas-independent and nonapoptotic pathway. The present study thus describes a novel mechanism of cytotoxicity mediated by CD4+ CTL.

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