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 (3–6) 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.
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Acknowledgements
We thank members of the Winoto, Allison, Robey and Raulet groups for discussions; P. Schow for technical assistance; A. Nagy, R. Nagy and W. Abramow-Newerly for the R1 ES cells; R.Jaenisch for the J1 ES cells; and E. Robey, B. Ortiz and H. Kasler for critical reading of the manuscript. This work is supported in part by grants from the NIH, National Science foundation and the Keck Foundation. J.Z. was supported by an Irvington Institute fellowship and is a Leukemia Society of America special fellow.
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Zhang, J., Cado, D., Chen, A. et al. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998). https://doi.org/10.1038/32681
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DOI: https://doi.org/10.1038/32681
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