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

Nature. 1998 Mar 19;392(6673):296-300. doi: 10.1038/32681.


Programmed cell death, or apoptosis, is important in homeostasis of the immune system: for example, non-functional or autoreactive 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 homeostasis. FADD/Mort1 is a Fas-associated protein that is thought to mediate apoptosis by recruiting the protease caspase-8. A dominant-negative mutant of FADD inhibits apoptosis initiated by Fas and other TNFR family members. Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway. 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 beta-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis*
  • B-Lymphocytes / cytology
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Division
  • DNA-Binding Proteins / genetics
  • Fas-Associated Death Domain Protein
  • Fetal Death
  • Flow Cytometry
  • Homeodomain Proteins*
  • Interleukin-2 / immunology
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Restriction Mapping
  • Stem Cells
  • T-Lymphocytes / immunology*
  • Thymus Gland / cytology
  • Transplantation Chimera
  • fas Receptor / physiology*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Homeodomain Proteins
  • Interleukin-2
  • fas Receptor
  • RAG-1 protein