T cell-specific FADD-deficient mice: FADD is required for early T cell development

FADD/Mort1, initially identified as a Fas-associated death-domain containin g protein, functions as an adapter molecule in apoptosis initiated by Fas, tumor necrosis factor receptor-I, DR3, and TRAIL-receptors, However, FADD l ikely participates in additional signaling cascades. FADD-null mutations in mice are embryonic-lethal, and analysis of FADD(-/-) T cells from RAG-1(-/ -) reconstituted chimeras has suggested a role for FADD in proliferation of mature T cells. Here, we report the generation of T cell-specific FADD-def icient mice via a conditional genomic rescue approach. We find that FADD-de ficiency leads to inhibition of T cell development at the CD4(-)CD8(-) stag e and a reduction in the number of mature T cells, The FADD mutation does n ot affect apoptosis or the proximal signaling events of the pre-T cell rece ptor; introduction of a T cell receptor transgene fails to rescue the mutan t phenotype, These data suggest that FADD, through either a death-domain co ntaining receptor or a novel receptor-independent mechanism, is required fo r the proliferative phase of early T cell development.