Down-regulation of normal human T cell blast activation: roles of APO2L/TRAIL, FasL, and c- FLIP, Bim, or Bcl-x isoform expression

A systematic study was undertaken to characterize the role of APO 2 ligand/tumor necrosis factor‐related apoptosis‐inducing ligand (APO2L/TRAIL) and Fas ligand (FasL) together with the expression of several anti‐ or proapoptotic proteins in the down‐regulation of normal human T cell responses. We ha...

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Published in:	Journal of leukocyte biology Vol. 77; no. 4; pp. 568 - 578
Main Authors:	Bosque, Alberto, Pardo, Julián, Martínez‐Lorenzo, Mª José, Iturralde, María, Marzo, Isabel, Piñeiro, Andrés, Alava, Mª Angeles, Naval, Javier, Anel, Alberto
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-04-2005
Subjects:	Antigens, CD - immunology Apoptosis Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 bcl-X Protein Carrier Proteins - genetics CASP8 and FADD-Like Apoptosis Regulating Protein Cell Death Fas Ligand Protein Gene Expression Regulation - immunology growth arrest Humans Intracellular Signaling Peptides and Proteins - genetics Lymphocyte Activation - immunology Membrane Glycoproteins - genetics Membrane Proteins - genetics Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins c-bcl-2 - genetics T lymphocytes T-Lymphocytes - immunology TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha - genetics
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Summary:	A systematic study was undertaken to characterize the role of APO 2 ligand/tumor necrosis factor‐related apoptosis‐inducing ligand (APO2L/TRAIL) and Fas ligand (FasL) together with the expression of several anti‐ or proapoptotic proteins in the down‐regulation of normal human T cell responses. We have observed for the first time that the higher sensitivity of normal human T cell blasts to apoptosis and activation‐induced cell death (AICD) as compared with naïve T cells correlates with the increased expression of Bcl‐x short (Bcl‐xS) and Bim. T cell blasts die in the absence of interleukin 2 (IL‐2) with no additional effect of death receptor ligation. In the presence of IL‐2, recombinant APO2L/TRAIL or cytotoxic anti‐Fas monoclonal antibodies induce rather inhibition of IL‐2‐dependent growth and not cell death on normal human T cell blasts. This observation is of physiological relevance, as supernatants from T cell blasts, pulse‐stimulated with phytohemagglutinin (PHA) or through CD3 or CD59 ligation and containing bioactive APO2L/TRAIL and/or FasL expressed on microvesicles or direct CD3 or CD59 ligation, had the same effect. Cell death was only observed in the presence of cycloheximide or after a pulse through CD3 or CD59, correlating with a net reduction in cellular Fas‐associated death domain‐like IL‐1β‐converting enzyme‐inhibitory protein long (c‐FLIPL) and c‐FLIPS expression. We also show that death receptor and free radical generation contribute, at least partially, to AICD induced by PHA and also to the inhibition of IL‐2‐dependent cell growth by CD3 or CD59 ligation. Finally, we have also shown that T cell blasts surviving PHA‐induced AICD are memory CD44high cells with increased c‐FLIPS and Bcl‐xL expression.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.0904514