ArticleNature communications2019
Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.
Erratum issuedOpen access · goldAbstract read
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Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 49 papers, 1 of them a synthesis that pooled it.
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49citing papers in PubMed, 1 pooled it
3.3field-weighted citation impact, top 7% of its field
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Who cites it
49 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review.Clinical and experimental immunology · 2021Pooled it
- Clinical Spectrum and Therapeutic Options in Monogenic CTLA-4-, LRBA-, or SOCS1-Related Primary Immune Regulatory Disorders.The journal of allergy and clinical immunology. In practice · 2026Review
- Digital spatial profiling uncovers transcriptomic features of distinct plasma cell-like phenotypes in diffuse large B-cell lymphoma.Blood advances · 2026Article
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- An imbalance between CD80 and CD86 levels and CD4 regulatory T cell number and transendocytosis function exists in the liver in autoimmune hepatitis.Clinical and experimental immunology · 2026Article
- Inborn errors of regulatory T-cell differentiation and function.The Journal of allergy and clinical immunology · 2025Review
- Proteostasis of immune checkpoint receptors.The Biochemical journal · 2025Review
- Rheumatologic and Autoimmune Features of Inborn Errors of Immunity: Implications for Diagnosis and Management.Journal of human immunity · 2025Article
- Article
- Exosomes from Tregs mitigate lung damage caused by smoking via inhibiting inflammation and altering T lymphocyte subsets in COPD rats.BMC pulmonary medicine · 2025Article
- Abatacept Induces Long-Term Reconstitution of the B-Cell Niche in a Patient With CTLA-4 Haploinsufficiency: A Case Report.Neurology(R) neuroimmunology & neuroinflammation · 2025Article
- Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans.Blood advances · 2025Article
- Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts.American journal of human genetics · 2025Article
- Tregopathy in focus.Frontiers in immunology · 2025Article
- An IL-2 mutein increases regulatory T cell suppression of dendritic cells via IL-10 and CTLA-4 to promote T cell anergy.Cell reports · 2024Article
- Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both?Molecular and cellular pediatrics · 2024Review
- Infections in Disorders of Immune Regulation.Pathogens (Basel, Switzerland) · 2024Review
- Review
- Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans.Frontiers in immunology · 2024Review
Corrections and comments
- Erratum issued
Authors and funding
42 authors at 12 institutions in 6 countries.
Nina K SerwasLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.ORCID http://orcid.org/0000-0003-2243-5446
Birgit HoegerLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.ORCID http://orcid.org/0000-0001-7491-9405
Rico C ArdyLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Sigrun V StulzCentre for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Zhenhua SuiDivision of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
Nima MemaranDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.ORCID http://orcid.org/0000-0002-9510-3154
Marie MeethsChildhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Ana KroloLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Özlem Yüce PetronczkiLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Laurène PfajferLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Tie Z HouInstitute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.
Neil HallidayInstitute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.ORCID http://orcid.org/0000-0001-8220-9139
Elisangela Santos-ValenteCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Artem KalinichenkoLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Alan KennedyInstitute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.ORCID http://orcid.org/0000-0003-0384-3866
Emily M MaceDepartment of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.
Malini MukherjeeDepartment of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.
Bianca TesiClinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Anna SchrempfCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Winfried F PicklInstitute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Joanna I LoizouCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Renate KainClinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.ORCID http://orcid.org/0000-0002-2428-543X
Bettina Bidmon-FliegenschneeDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Jean-Nicolas SchickelDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA.
Salomé GlauzyDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA.
Jakob HuemerLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Wojciech GarncarzLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Elisabeth SalzerLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Iro PieridesLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Ivan BilicCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Jens ThielDepartment of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, 79106, Germany.
Peter PriftakisAstrid Lindgren Children's Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Pinaki P BanerjeeDepartment of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.
Elisabeth Förster-WaldlDepartment of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria.ORCID http://orcid.org/0000-0002-8484-9890
David MedgyesiLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Wolf-Dietrich HuberDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Jordan S OrangeDepartment of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.
Eric MeffreDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA.
David M SansomInstitute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.ORCID http://orcid.org/0000-0001-6506-3115
Yenan T BrycesonCentre for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-7783-9934
Amnon AltmanDivision of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
Kaan BoztugLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. kaan.boztug@ccri.at.
Austrian Academy of Sciences · ATKarolinska University Hospital · SEMedical University of Vienna · ATThe Royal Free Hospital · GBBaylor College of Medicine · USYale University · USLa Jolla Institute for Immunology · USCentre National de la Recherche Scientifique · FRMedizinische Hochschule Hannover · DESt Anna Children's Hospital · ATThe University of Texas MD Anderson Cancer Center · USUniversity Medical Center Freiburg · DE
Funding
Regulation of IgA class switching in the intestinal mucosaP01AI061093 · NIAID · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI CUNNINGHAM-RUNDLES, CHARLOTTE · 2004 to 2021
$29.8MSLAT: A novel GEF coordinating actin remodeling and Ca2+ signaling in T cellsR01AI068320 · NIAID · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI ALTMAN, AMNON · 2006 to 2015
$4.5MTraining in Immunological MechanismsT32AI125179 · NIAID · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI CROFT, MICHAEL · 2016 to 2025
$3.1MAustrian Science Fund FWF P 24999Austrian Science Fund FWF P 29951NIAID NIH HHS P01 AI061093NIAID NIH HHS R01 AI068320NIAID NIH HHS T32 AI125179
Abstract
Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11
Indexed as
B7-1 AntigenCTLA-4 AntigenDNA-Binding ProteinsGene Knockout TechniquesGuanine Nucleotide Exchange FactorsHomeostasisHumansJurkat CellsPrimary Immunodeficiency Diseasesrab11 GTP-Binding Proteinsrab GTP-Binding ProteinsT-LymphocytesB7-1 AntigenCTLA-4 AntigenDEF6 protein, humanDNA-Binding ProteinsGuanine Nucleotide Exchange Factorsrab11 GTP-Binding Proteinsrab GTP-Binding Proteins
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.