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Published online before print January 14, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0904514

Received for publication September 15, 2004.
Revised November 15, 2004.
Accepted for publication December 9, 2004.

Article

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

Alberto Bosque ^*, Julián Pardo ^*, Mª José Martínez-Lorenzo , María Iturralde ^*, Isabel Marzo ^*, Andrés Piñeiro ^*, Mª Angeles Alava ^*, Javier Naval ^*, and Alberto Anel ^*@

*Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, and Servicio de Inmunología, Hospital Clínico Universitario, Universidad de Zaragoza, Spain

^@ To whom correspondence should be addressed. E-mail: anel{at}posta.unizar.es.

	Abstract

A systematic study was undertaken to characterize the role of apolipoprotein 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-x_S) 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 than inhibit 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-1-converting enzyme-inhibitory protein long (c-FLIP_L) and c-FLIP_S 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 CD44^high cells with increased c-FLIP_S and Bcl-x_L expression.

Key Words: T lymphocytes • growth arrest • apoptosis

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