Requirement for Daxx in mature T-cell proliferation and activation

• Published in: Cell death and differentiation Vol. 14; no. 4; pp. 795 - 806
• Main Authors: Leal-Sanchez, J, Couzinet, A, Rossin, A, Abdel-Sater, F, Chakrabandhu, K, Luci, C, Anjuere, F, Stebe, E, Hancock, D, Hueber, A-O
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2007
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens, CD95; Apoptosis; Apoptosis - physiology; Biochemistry, Molecular Biology; Cancer; Cancer research; Carrier Proteins; Carrier Proteins - metabolism; Caspases; Caspases - metabolism; Cell death; Cell growth; Cell Proliferation; Developmental biology; Fas Ligand Protein; Fas Ligand Protein - metabolism; fas Receptor - physiology; Genes, Dominant; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases - metabolism; Jurkat Cells; Kinases; Life Sciences; Lymphatic system; Lymphocyte Activation; Lymphocytes; Medical research; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases - metabolism; Molecular biology; Nuclear Proteins; Nuclear Proteins - metabolism; Proteins; T-Lymphocytes; T-Lymphocytes - chemistry; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Thymus gland; Transgenic animals; France
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4402056

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.