Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0108043 on May 15, 2008

Published online before print May 15, 2008
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(Journal of Leukocyte Biology. 2008;84:488-498.)
© 2008 by Society for Leukocyte Biology

Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes

Alberto Bosque*,1, Juan I. Aguiló*, Manuel del Rey{dagger}, Estela Paz-Artal{dagger}, Luis M. Allende{dagger}, Javier Naval* and Alberto Anel*,2

* Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; and
{dagger} Servicio de Inmunología, Hospital 12 de Octubre, Madrid, Spain

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

The Fas-FasL pathway plays an important role in the homeostasis of mature lymphocytes, with defects causing autoimmune lymphoproliferative syndromes (ALPS). Human T-cell blasts are not sensitive to FasL or Apo2L/TRAIL-induced apoptosis unless they get reactivated, but either of those ligands inhibits their growth in the absence of cell death induction due to a cell cycle arrest in S-G2/M. In the present work, we have studied the mechanism(s) by which FasL or Apo2L/TRAIL regulate T-cell blast cell cycle in healthy donors and in two types of ALPS patients. Our data indicate that in human CD8+ T-cell blasts, Fas ligation, and especially Apo2L/TRAIL induce the p53-dependent decrease in cyclin-B1 levels. However, the induction of the negative cell cycle regulator p21WAF1 by FasL or Apo2L/TRAIL in either CD4+ or CD8+ T-cell blasts seems to be the main regulatory mechanism. This mechanism is dependent on caspase activation and on H2O2 generation. The increase in p21 levels by FasL or Apo2L/TRAIL is concomitant with p53 increases only in CD8+ T-cell blasts, with p21 levels maintained high for longer times than p53 levels. In CD4+ T-cell blasts p21 levels are controlled through a transient and p53-independent mechanism. The present results suggest that the etiology of ALP syndromes could be related not only to defects in apoptosis induction, but also in cell cycle regulation.

Key Words: lymphocyte proliferation • lymphocyte homeostasis • autoimmunity • death receptors






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