HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print January 14, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: jlb.0904514v1 77/4/568    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bosque, A. Articles by Anel, A. Search for Related Content PubMed PubMed Citation Articles by Bosque, A. Articles by Anel, A.

(Journal of Leukocyte Biology. 2005;77:568-578.)
© 2005 by Society for Leukocyte Biology

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^*,1

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

¹ Correspondence: Dept. Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, E-50009, Spain. E-mail: anel{at}posta.unizar.es

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-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 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-1ß-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

This article has been cited by other articles:

				A. Bosque, J. I. Aguilo, M. del Rey, E. Paz-Artal, L. M. Allende, J. Naval, and A. Anel Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes J. Leukoc. Biol., August 1, 2008; 84(2): 488 - 498. [Abstract] [Full Text] [PDF]

				A. Meinander, T. S. Soderstrom, A. Kaunisto, M. Poukkula, L. Sistonen, and J. E. Eriksson Fever-Like Hyperthermia Controls T Lymphocyte Persistence by Inducing Degradation of Cellular FLIPshort J. Immunol., March 15, 2007; 178(6): 3944 - 3953. [Abstract] [Full Text] [PDF]

				A. Bosque, J. I. Aguilo, M. A. Alava, E. Paz-Artal, J. Naval, L. M. Allende, and A. Anel The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling Blood, February 15, 2007; 109(4): 1627 - 1635. [Abstract] [Full Text] [PDF]

				K. J. Rautajoki, E. M. Marttila, T. A. Nyman, and R. Lahesmaa Interleukin-4 Inhibits Caspase-3 by Regulating Several Proteins in the Fas Pathway during Initial Stages of Human T Helper 2 Cell Differentiation Mol. Cell. Proteomics, February 1, 2007; 6(2): 238 - 251. [Abstract] [Full Text] [PDF]

				K. Laudanski, C. Miller-Graziano, W. Xiao, M. N. Mindrinos, D. R. Richards, A. De, L. L. Moldawer, R. V. Maier, P. Bankey, H. V. Baker, et al. Cell-specific expression and pathway analyses reveal alterations in trauma-related human T cell and monocyte pathways PNAS, October 17, 2006; 103(42): 15564 - 15569. [Abstract] [Full Text] [PDF]

				M. Del-Rey, J. Ruiz-Contreras, A. Bosque, S. Calleja, J. Gomez-Rial, E. Roldan, P. Morales, A. Serrano, A. Anel, E. Paz-Artal, et al. A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome Blood, August 15, 2006; 108(4): 1306 - 1312. [Abstract] [Full Text] [PDF]

				D. C. Neujahr, C. Chen, X. Huang, J. F. Markmann, S. Cobbold, H. Waldmann, M. H. Sayegh, W. W. Hancock, and L. A. Turka Accelerated Memory Cell Homeostasis during T Cell Depletion and Approaches to Overcome It. J. Immunol., April 15, 2006; 176(8): 4632 - 4639. [Abstract] [Full Text] [PDF]