Document Detail

The death receptor pathway is not involved in alloreactive T-cell induced mitochondrial membrane permeability.
MedLine Citation:
PMID:  16085564     Owner:  NLM     Status:  MEDLINE    
Elimination of tumor cells by cytotoxic T lymphocytes (CTL) is mediated by two major pathways: the granule exocytosis and the death receptor pathway, transduced by Fas, TNF and TRAIL. The usage of these distinct pathways in the alloreactive setting across major and minor HLA barriers still remains controversial. We generated CTLs against allogeneic Epstein-Barr virus (EBV)-transformed cell lines (LCL) from HLA-unmatched healthy donors and assessed their cytotoxicity by flow cytometrically measuring mitochondrial membrane permeability (MMP) of target cells. Mitochondrial apoptosis induced by CTL was abrogated by selectively inhibiting the granule exocytosis-mediated pathway with Concanamycin A (CMA). Conversely, apoptosis was not decreased in the presence of the caspase 8 inhibitor IETD, which is specific for all death receptor pathways. In general, caspases were not involved in MMP as shown using the pan-caspase inhibitor zVAD. This effector mechanism was preserved when using purified CD4 + and CD8 + T-lymphocyte subsets to generate CTL. We further showed, that death receptor signalling was not used as a salvage mechanism when granule exocytosis was inhibited even at longer incubation times sufficient for slow kinetic death receptor caspase signalling. Our results clearly demonstrate that mitochondrial apoptosis induced by human alloreactive CTLs is mainly mediated by granule exocytosis but not by death receptor caspase dependent pathways. Furthermore, the granule exocytosis pathway does not require caspases to induce MMP.
Carsten Grüllich; Suzanne McGoldrick; Robert Zeiser; Jürgen Finke
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia & lymphoma     Volume:  46     ISSN:  1042-8194     ISO Abbreviation:  Leuk. Lymphoma     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-08     Completed Date:  2006-04-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9007422     Medline TA:  Leuk Lymphoma     Country:  England    
Other Details:
Languages:  eng     Pagination:  1207-16     Citation Subset:  IM    
Division of Haematology/Oncology, Daprtment of Medicine, Freiburg University Hospital, University of Freiburg, Germany.
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MeSH Terms
Antigens, CD95 / immunology
Apoptosis / drug effects
Caspases / antagonists & inhibitors
Cell Line, Transformed
Coumarins / pharmacology
Cysteine Proteinase Inhibitors / pharmacology
Cytotoxicity Tests, Immunologic
Intracellular Membranes / drug effects,  immunology*
Macrolides / pharmacology
Mitochondria / drug effects,  immunology*
Oligopeptides / pharmacology
Permeability / drug effects
Receptors, Tumor Necrosis Factor / immunology*
Signal Transduction / immunology*
T-Lymphocytes, Cytotoxic / immunology*
Reg. No./Substance:
0/Antigens, CD95; 0/Coumarins; 0/Cysteine Proteinase Inhibitors; 0/Macrolides; 0/Oligopeptides; 0/Receptors, Tumor Necrosis Factor; 51050-59-0/3,4-dichloroisocoumarin; 80890-47-7/concanamycin A; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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