FAS-MEDIATED APOPTOSIS AND ACTIVATION-INDUCED T-CELL PROLIFERATION ARE DEFECTIVE IN MICE LACKING FADD MORT1/

Programmed cell death, or apoptosis, is important in homeostasis of th e immune system: for example, non-functional or autoreactive lymphocyt es are eliminated through apoptosis, One member of the tumour necrosis factor receptor (TNFR) family; Fas (also known as CD95 or Apo-1), can trigger cell death and is essential for lymphocyte homeostasis(1,2). FADD/Mort1 (refs 3-6) is a Pas-associated protein that is thought to m ediate apoptosis by recruiting the protease caspase-8 (refs 7, 8), A d ominant-negative mutant of FADD inhibits apoptosis initiated by Fas an d other TNFR family members(6,9-14). Other proteins, notably Daax, als o bind Fas and presumably mediate a FADD-independent apoptotic pathway (15). Here we investigate the role of FADD in vivo by generating FADD- deficient mice. As homozygous mice die in utero, we generated FADD(-/- ) embryonic stem cells and FADD(-/-) chimaeras in a background devoid of the recombination activating gene RAG-1, which activates rearrangem ent of the immunoglobulin and T-cell receptor genes, We found that thy mocyte subpopulations were apparently normal in newborn chimaeras. Fas -induced apoptosis was completely blocked, indicating that there are n o redundant Fas apoptotic pathways, As these mice age, their thymocyte s decrease to an undetectable level, although peripheral T cells are p resent in all older FADD(-/-) chimaeras, Unexpectedly, activation-indu ced proliferation is impaired in these FADD(-/-) T cells, despite prod uction of the cytokine interleukin (IL)-2, These results and the simil arities between FADD(-/-) mice and mice lacking the P-subunit of the I L-2 receptor suggest that there is an unexpected connection between ce ll proliferation and apoptosis.