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

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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. 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data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Hyung_J_-Chun-Aff1" data-author-popup="auth-Hyung_J_-Chun-Aff1" data-author-search="Chun, Hyung J.">Hyung J. Chun</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Lixin-Zheng-Aff1" data-author-popup="auth-Lixin-Zheng-Aff1" data-author-search="Zheng, Lixin">Lixin Zheng</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Manzoor-Ahmad-Aff1" data-author-popup="auth-Manzoor-Ahmad-Aff1" data-author-search="Ahmad, Manzoor">Manzoor Ahmad</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Jin-Wang-Aff1-Aff6" data-author-popup="auth-Jin-Wang-Aff1-Aff6" data-author-search="Wang, Jin">Jin Wang</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup><sup class="u-js-hide"> <a href="#nAff6">nAff6</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Christina_K_-Speirs-Aff1" data-author-popup="auth-Christina_K_-Speirs-Aff1" data-author-search="Speirs, Christina K.">Christina K. 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Hall</a><sup class="u-js-hide"><a href="#Aff3">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Suzanne-Skoda_Smith-Aff3" data-author-popup="auth-Suzanne-Skoda_Smith-Aff3" data-author-search="Skoda-Smith, Suzanne">Suzanne Skoda-Smith</a><sup class="u-js-hide"><a href="#Aff3">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-T__Prescott-Atkinson-Aff3" data-author-popup="auth-T__Prescott-Atkinson-Aff3" data-author-search="Atkinson, T. Prescott">T. 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Lenardo<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 419</b>, <span class="u-visually-hidden">pages </span>395–399 (<span data-test="article-publication-year">2002</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">4391 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">549 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">14 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nature01063/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>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 autoimmunity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Abbas, A. K. Die and let live: eliminating dangerous lymphocytes. Cell 84, 655–657 (1996)" href="/articles/nature01063#ref-CR1" id="ref-link-section-d87329851e532">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Lenardo, M. et al. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999)" href="/articles/nature01063#ref-CR2" id="ref-link-section-d87329851e535">2</a></sup>. 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 complex<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Wang, J., Chun, H. J., Wong, W., Spencer, D. M. & Lenardo, M. J. Caspase-10 is an initiator caspase in death receptor signaling. Proc. Natl Acad. Sci. USA 98, 13884–13888 (2001)" href="/articles/nature01063#ref-CR3" id="ref-link-section-d87329851e539">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Kischkel, F. C. et al. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J. Biol. Chem. 276, 46639–46646 (2001)" href="/articles/nature01063#ref-CR4" id="ref-link-section-d87329851e542">4</a></sup>. 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 autoimmunity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Fisher, G. H. et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81, 935–946 (1995)" href="/articles/nature01063#ref-CR5" id="ref-link-section-d87329851e546">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Rieux-Laucat, F. et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. 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Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98, 47–58 (1999)" href="/articles/nature01063#ref-CR11" id="ref-link-section-d87329851e565">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Alam, A., Cohen, L. Y., Aouad, S. & Sekaly, R. P. Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J. Exp. Med. 190, 1879–1890 (1999)" href="/articles/nature01063#ref-CR12" id="ref-link-section-d87329851e568">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Kennedy, N. J., Kataoka, T., Tschopp, J. & Budd, R. C. Caspase activation is required for T cell proliferation. J. Exp. Med. 190, 1891–1896 (1999)" href="/articles/nature01063#ref-CR13" id="ref-link-section-d87329851e571">13</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Posmantur, R., Wang, K. K. & Gilbertsen, R. B. Caspase-3-like activity is necessary for IL-2 release in activated Jurkat T-cells. Exp. Cell Res. 244, 302–309 (1998)" href="/articles/nature01063#ref-CR14" id="ref-link-section-d87329851e574">14</a></sup>. 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.</p></div></div></section> <noscript> <div class="c-nature-box c-nature-box--side " data-component="entitlement-box"> <div class="js-access-button"> <a href="https://wayf.springernature.com?redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnature01063" class="c-article__button" data-test="ra21"> <svg class="u-icon" width="18" height="18" aria-hidden="true" focusable="false"><use href="#icon-institution"></use></svg> <span class="c-article__button-text">Access through your institution</span> </a> </div> <div class="js-buy-button"> <a href="#access-options" class="c-article__button c-article__button--inverted" data-test="ra21"> <span>Buy or subscribe</span> </a> </div> </div> </noscript> <div class="js-context-bar-sticky-point-mobile" data-track-context="article body"> </div> <div class="c-article-access-provider u-mb-32 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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.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="nAff6"><p class="c-article-author-information__authors-list">Jin Wang</p><p class="js-present-address">Present address: Baylor College School of Medicine, Houston, Texas, USA</p></li><li class="c-article-author-information__item" id="nAff7"><p class="c-article-author-information__authors-list">Richard M. Siegel</p><p class="js-present-address">Present address: Immunoregulation Unit, Autoimmune Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA</p></li><li class="c-article-author-information__item" id="na1"><p>Hyung J. Chun, Lixin Zheng, Manzoor Ahmad, Jennifer Puck and Joie Davis: These authors contributed equally to this work</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA</p><p class="c-article-author-affiliation__authors-list">Hyung J. Chun, Lixin Zheng, Manzoor Ahmad, Jin Wang, Christina K. Speirs, Richard M. Siegel & Michael J. Lenardo</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA</p><p class="c-article-author-affiliation__authors-list">Janet K. Dale & Stephen E. Straus</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA</p><p class="c-article-author-affiliation__authors-list">Jennifer Puck & Joie Davis</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, 35294, USA</p><p class="c-article-author-affiliation__authors-list">Craig G. Hall, Suzanne Skoda-Smith & T. 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