FADD-deficient T cells exhibit a disaccord in regulation of the cell cyclemachinery

FADD is an adapter protein that was originally isolated as a transducer of apoptotic signals for death domain-containing receptors. However, FADD-defi cient mice are embryonic lethal and FADD(-/-) T cells developed from FADD(- /-) embryonic stem cells in the RAG-1(-/-) hosts lack the full potential to proliferate when stimulated through their T-cell receptor complex, suggest ing that FADD protein might play a dualistic role in mediating not only cel l death signaling but other non-apoptotic cellular pathways as well. Here w e show that a substantial number of freshly isolated FADD(-/-) peripheral T cells are cycling but are defective in their co-stimulatory response when stimulated. Analysis of several cell cycle proteins shows normal down-regul ation of p27 inhibitor but increased levels of p21, decreased levels of cyc lin D2, and constitutive activation of several cyclin-dependent kinases in activated T cells. These data suggest that FADD is involved in the regulati on of cell cycle machinery in T lymphocytes.