T cell proliferative and apoptotic responses in conditional Daxx knockout mice (163.16)

Abstract

Abstract Apoptosis is essential for maintaining homeostasis in the immune system. Fas is a single transmembrane domain protein capable of inducing apoptotic death in lymphocytes. Mutations in the Fas receptor or it’s ligand, FasL, lead to autoimmune-lymphocproliferation diseases characterized by lymphadenopathy, splenomegaly and autoantibody production. The Fas-associated death domain (FADD) protein is an adaptor protein which binds to Fas, recruits and activates the initiator caspase 8. In addition to FADD, proteins including Daxx have also been indicated to bind to Fas. It has been proposed that Daxx mediates a parallel apoptotic pathway that is independent of FADD and Caspase 8, but is dependent on ASK1-medaited signaling. Deletion of FADD blocks Fas-induced apoptosis in T and B cells, which, however, does not lead to lymphoproliferation diseases as present in Fas mutant animals. Recent studies indicate that absence of FADD unleashes a potent necrosis-like death pathway. The in vivo function of Daxx in lymphocytes has not been properly analyzed as deletion of Daxx in germ cells lead to embryonic lethality. In this study, we used a conditional mutant mouse in which Daxx is deleted specifically in T cells. Our data revealed a novel function of Daxx in the regulation of proliferation and death in primary T cells.