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

Nature volume 392, pages 296–300 (1998)Cite this article

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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Figure 1: Targeted inactivation of the gene encoding FADD/Mort1 in ES cells and in mice.
Figure 2: Flow cytometric analysis of thymocytes from wild-type 129/Sv × B6, RAG-1−/−, FADD−/− to RAG-1−/− (FADD−/−), and FADD+/+ to RAG-1−/− (FADD+/+) mice.
Figure 3: Flow cytometric analysis of peripheral lymphocytes.
Figure 4: Fas-mediated cell death is blocked in the absence of FADD.
Figure 5: T-cell proliferation and death and IL-2 secretion assay.

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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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  1. Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California at Berkeley, 469 LSA, Berkeley, 94720-3200, California, USA

    Jianke Zhang, Dragana Cado, Ann Chen, Nisha H. Kabra & Astar Winoto

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  1. Jianke Zhang
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Correspondence to Astar Winoto.

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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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