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

J Zhang, D Cado, A Chen, NH Kabra, A Winoto - Nature, 1998 - nature.com
J Zhang, D Cado, A Chen, NH Kabra, A Winoto
Nature, 1998nature.com
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 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 …
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 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 β-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.
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