Submitted May 11, 2006
Accepted August 16, 2006
The induction of Bim expression in human T cell blasts is dependent on non-apoptopic Fas/CD95 signalling
Alberto Bosque, Juan Ignacio Aguilo, Maria Angeles Alava, Estela Paz-Artal, Javier Naval, Luis M Allende, and Alberto Anel*
Departamento de Bioquimica y Biologia Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
Servicio de Inmunologia, Hospital 12 de Octubre, Madrid, Spain
* Corresponding author; email: anel{at}posta.unizar.es.
The BH3-only protein Bim is required for maintaining the homeostasis of the immune system, since it regulates the down-modulation of T cell responses, mainly through cytokine deprivation. Using T cell blasts from healthy donors and also from patients with autoimmune lymphoproliferative syndromes (ALPS) due to homozygous loss-of-function mutation of FasL (ALPS-Ic) or heterozygous mutation in the Fas/CD95 death domain (ALPS-Ia), it is shown that the induction of Bim expression during the process of human T cell blast generation is strictly dependent on FasL/Fas-mediated signalling. The main pathway by which Fas signalling regulates the levels of Bim expression in human T cell blasts is the death-domain- and caspase-independent generation of discrete levels of H2O2, which results in the net increase of Foxo3a levels. The present results connect the two main pathways described until the moment for the control of T cell responses: death receptor-mediated activation-induced cell death and apoptosis by cytokine deprivation.
