Requirement for Daxx in mature T-cell proliferation and activation

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 TCRinduced cell proliferation and by promoting Fas-mediated cell death.

Distribution and location of Daxx in cervical epithelial cells with high risk human papillomavirus positive

“…It is a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death [10]. Daxx has been shown that it acts as a scaffold that stimulates the phosphorylation of p53 by the protein kinase Hipk2 [11].…”

Germinal center kinases in immune regulation

“…33 As a novel histone chaperone and a product of an interferon-c-induced gene, Daxx has been extensively implicated in virus infection and T-cell activation. [34][35][36][37][38][39][40][41][42][43] Recent studies demonstrated that MST1 and Daxx interact with each other to mediate interferon-c-induced apoptosis in microglia, which plays a critical role during inflammation. 44 In this process, Daxx directly binds to MST1 and regulates its homooligomerization, activation and nuclear translocation.…”

Daxx plays a novel role in T cell survival but is dispensable in Fas-induced apoptosis

“…Prior studies depended largely on the use of a dominant negative Daxx mutant, which may have unintended effects [20–22]. For example, using the same Daxx-DN mutant, two independent studies reached opposing conclusions regarding the function of Daxx in Fas-induced apoptosis [27,28]. To date, the only other available system is a mouse Daxx -/- embryonic stem cell line, which was used in understanding a Fas-independent function for Daxx in controlling Mdm2 stability [37].…”

“…However, a subsequent study indicated that Daxx-DN inhibited Fas-induced apoptosis in primary T cells [28]. Therefore, whether Daxx plays a role in the Fas-signaling pathway has remained an unresolved issue.…”