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Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency

Nature volume 419, pages 395–399 (2002)Cite this article

Abstract

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity1,2. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex3,4. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity5,6,7,8,9,10,11,12,13,14. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.

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Figure 1: Defective apoptosis and DISC analysis in family 66.
Figure 2: Characterization of an inherited caspase-8 mutation.
Figure 3: Defective immune cell responses in homozygous caspase-8 mutants.
Figure 4: Caspase-8 is required for lymphocyte activation.

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Acknowledgements

We thank R. Germain, L. Staudt and P. Schwartzberg for critically reading the manuscript; J. Blenis, M. Peter, M. Finer, M. Roberts, D. Chinnasamy and F. Candotti for materials and reagents; D. Stephany, K. Holmes, R. Swofford and S. Tartt for flow cytometry assistance; T. Fleisher for immunophenotyping; R. Fischer for EBV cell lines; W. Strober, F. Dugan and D. Smith for clinical assistance; S. Rajagopalan and E. Long for advice and antibodies; M. Tibbetts and C. Trageser for technical assistance; J. Sung and B. Bierer for assistance with luciferase assays; N. Thekdi for discussions; Amaxa Biosystems for materials and assistance; and Pharmingen-BD Biosciences for donating antibodies for lymphocyte surface markers. H.J.C. is a Howard Hughes Medical Institute-National Institutes of Health Research Scholar.

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Author notes

  1. Jin Wang

    Present address: Baylor College School of Medicine, Houston, Texas, USA

  2. Richard M. Siegel

    Present address: Immunoregulation Unit, Autoimmune Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

  3. Hyung J. Chun, Lixin Zheng, Manzoor Ahmad, Jennifer Puck and Joie Davis: These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Hyung J. Chun, Lixin Zheng, Manzoor Ahmad, Jin Wang, Christina K. Speirs, Richard M. Siegel & Michael J. Lenardo

  2. Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Janet K. Dale & Stephen E. Straus

  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Jennifer Puck & Joie Davis

  4. University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, 35294, USA

    Craig G. Hall, Suzanne Skoda-Smith & T. Prescott Atkinson

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Correspondence to Michael J. Lenardo.

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Chun, H., Zheng, L., Ahmad, M. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002). https://doi.org/10.1038/nature01063

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