1. ¹Equipe Labellisée par La Ligue Nationale Centre le Cancer Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Nice, France
2. ²Faculté de Médecine Pasteur, INSERM U721, Nice, France
3. ³Lincoln's Inn Fields Laboratories, London Research Institute, Cancer Research UK, London, UK

Correspondence: A-O Hueber, Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A. Lacassagne, 33, Avenue de Valombrose, 06189 Nice, France. Tel: +00 33 492031241; Fax: +00 33 492031245; E-mail: hueber@unice.fr

Received 21 April 2006; Revised 8 September 2006; Accepted 19 September 2006; Published online 3 November 2006.

Abstract

The protein Daxx promotes Fas-mediated cell death through activation of apoptosis signal-regulating kinase 1, leading to the activation of the MAPKs JNK and p38. Owing to the in utero lethality of daxx-deficient mice, the in vivo role of Daxx has been so far difficult to analyze. We have generated transgenic mice expressing a dominant-negative form of Daxx (Daxx-DN) in the T-cell lineage. We show that Daxx is recruited to the Fas receptor upon FasL engagement and that Daxx-DN expression protects activated T cells from Fas-induced cell death, by preventing the death-inducing signal complex to be properly formed. Normal lymphocyte development and homeostasis are nevertheless observed. Interestingly, we report that both in vitro and in vivo stimulation of Daxx-DN T-lymphocytes leads to increased proliferative T-cell responses. This increased proliferation is associated with a marked increase in tyrosine phosphorylation of LAT and ZAP70 as Daxx-DN favor their recruitment to the T-cell receptor (TCR) complex. These findings identify Daxx as a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death.