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J Leukoc Biol. 2008 Aug;84(2):488-98. doi: 10.1189/jlb.0108043. Epub 2008 May 15.

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

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  • 1Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza E-50009, Spain.


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.

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