Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1

Abstract

Programmed cell death, or apoptosis, is important in homeostasis of the immune system: for example, non-functional or auto-reactive lymphocytes 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 homeostasis¹,². FADD/Mort1 (3,​ 4,​ 5,​ 6) is a Fas-associated protein that is thought to mediate apoptosis by recruiting the protease caspase-8 (refs 7, 8). A dominant-negative mutant of FADD inhibits apoptosis initiated by Fas and other TNFR family members⁶,^{9,10,11,12,13,14}. Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway¹⁵. 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 rearrangement of the immunoglobulin and T-cell receptor genes. We found that thymocyte subpopulations were apparently normal in newborn chimaeras. Fas-induced apoptosis was completely blocked, indicating that there are no redundant Fas apoptotic pathways. As these mice age, their thymocytes decrease to an undetectable level, although peripheral T cells are present in all older FADD^−/− chimaeras. Unexpectedly, activation-induced proliferation is impaired in these FADD^−/− T cells, despite production of the cytokine interleukin (IL)-2. These results and the similarities between FADD^−/− mice and mice lacking the β-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.