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Cell cycle regulation by FasL and Apo2L/TRAIL in human T‐cell blasts. Implications for autoimmune lymphoproliferative syndromes
Author(s) -
Bosque Alberto,
Aguiló Juan I.,
Rey Manuel,
PazArtal Estela,
Allende Luis M.,
Naval Javier,
Anel Alberto
Publication year - 2008
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0108043
Subject(s) - fas ligand , cell cycle , biology , apoptosis , t cell , microbiology and biotechnology , cd8 , cell , immunology , programmed cell death , cancer research , immune system , biochemistry
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‐G 2 /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 p21 WAF1 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 H 2 O 2 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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