ArticleNature immunology2026
Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function.
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Article in Nature immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Toward a monogenic architecture of human infections: From 1996 to 2026.Journal of human immunity · 2026Review
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Authors and funding
86 authors.
Taja Vatovec *Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany.
Anna-Lena Neehus *Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8573-6820
Katherine J L JacksonGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9952-7069
Danielle T AveryGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9156-0489
Ivan BagarićGene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany.
Lucia ErazoLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Carlos A Arango-FrancoLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.ORCID http://orcid.org/0000-0002-7404-0860
Masato OgishiSt. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.
Syed F AhmedCancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.ORCID http://orcid.org/0000-0003-1033-2538
Axel CederholmScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0009-0006-5973-9637
Amanda J RussellGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-7148-1081
Erika Della MinaGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-8733-7623
Dena Al-RifaiGarvan Institute of Medical Research, Sydney, New South Wales, Australia.
Rowena BullGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9844-3744
Lori BuetowCancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.
Steicy SobrinoParis Cité University, Imagine Institute, Paris, France.
Allison ZhangDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Lara WahlsterDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Marine MicheletUnit of Allergy and Pneumology, Childrens Hospital, Toulouse, France.
Nima ParvanehDivision of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
Jessica PeelSt. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA.
Federica BarzaghiSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Davide LeardiniPediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.ORCID http://orcid.org/0000-0002-4673-5876
Quentin PhilippotLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Francesco SaettiniCentro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.ORCID http://orcid.org/0000-0003-0767-3905
Jacques DutrieuxUniversité Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
Benedicte de MuylderUniversité Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
Francesca VendeminiPediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Francesco BaccelliPediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Albert CatalaPediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
Eleonora GambineriDepartment of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.ORCID http://orcid.org/0000-0002-4676-6541
Marinella VeltroniDivision of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
Vignesh PandiarajanAllergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Yurena AguilarPediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain.ORCID http://orcid.org/0000-0002-4720-1198
Filomeen HaerynckDepartment of Pediatric Pulmonology, Infectious Diseases and Immunology, Ghent University Hospital, Ghent, Belgium.
Michael ElliottSydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
Stuart TurvilleGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-1918-5343
Fabienne BrillotGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-7025-2276
Taushif KhanCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Filippo ConsonniDivision of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.ORCID http://orcid.org/0000-0002-6879-8982
Laureline BertelootDepartment of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France.ORCID http://orcid.org/0000-0001-9681-3142
William A SewellGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-3586-8761
Geetha RaoGarvan Institute of Medical Research, Sydney, New South Wales, Australia.
Laetitia LargeaudLaboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France.
Francesca ContiPediatric Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy.
Cecile RoullionParis Cité University, Imagine Institute, Paris, France.
Cécile MassonParis Cité University, Imagine Institute, Paris, France.
Francesco PegoraroDivision of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
Tianyi YeDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Samantha JoubranDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Emily VillalpandoDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Boris BessotParis Cité University, Imagine Institute, Paris, France.
Yoann SeeleuthnerLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Tom Le VoyerLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.ORCID http://orcid.org/0000-0002-7253-3135
Jérémie RosainLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Hailun LiLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Zarah JandaLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.ORCID http://orcid.org/0009-0006-4784-0324
Edoardo MuratorePediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Camille SoudéeLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Eric DelabesseDepartment of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, University Paul-Sabatier Toulouse, Toulouse, France.ORCID http://orcid.org/0000-0002-0928-0753
Claire GoulvestreLaboratory of Immunology, Cochin Hospital, Paris, France.
Mohammad ShahrooeiDr. Shahrooei Lab, Tehran, Iran.
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.ORCID http://orcid.org/0000-0003-2603-0323
Isabelle AndréParis Cité University, Imagine Institute, Paris, France.ORCID http://orcid.org/0000-0002-3905-9910
Christine Bole-FeysotParis Cité University, Imagine Institute, Paris, France.
Laurent AbelLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Miriam ErlacherDivision of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Vivien BéziatLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.ORCID http://orcid.org/0000-0002-4020-824X
Chantal Lagresle-PeyrouParis Cité University, Imagine Institute, Paris, France.ORCID http://orcid.org/0000-0002-2216-6453
Remi CheynierUniversité Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.ORCID http://orcid.org/0000-0003-1146-660X
Emmanuelle SixParis Cité University, Imagine Institute, Paris, France.ORCID http://orcid.org/0000-0001-7806-0968
Nico MarrCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.ORCID http://orcid.org/0000-0002-1927-7072
Marlène PasquetDepartment of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.
Laia AlsinaClinical Immunology and Primary Immunodeficiences Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu Barcelona, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain.ORCID http://orcid.org/0000-0002-3559-0018
Christopher C GoodnowGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-5296-6155
Nils LandegrenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0002-6163-9540
Alessandro AiutiSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID http://orcid.org/0000-0002-5398-1717
Peng ZhangParis Cité University, Imagine Institute, Paris, France.ORCID http://orcid.org/0000-0002-6129-567X
Riccardo MasettiPediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Danny T HuangCancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.
Cindy S MaGarvan Institute of Medical Research, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-5387-8413
Jean-Laurent CasanovaLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Vijay G SankaranDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0044-443X
Jacinta BustamanteLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France.
Stuart G TangyeGarvan Institute of Medical Research, Sydney, New South Wales, Australia. s.tangye@garvan.org.au.ORCID http://orcid.org/0000-0002-5360-5180
Jonathan BohlenGene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany. bohlen@genzentrum.lmu.de.ORCID http://orcid.org/0000-0003-0458-9484
Funding
Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MSystematic Genetic Dissection of Human ErythropoiesisR01DK103794 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2014 to 2026
$5.9MNext generation functional genomics of hematology traitsR01HL146500 · NHLBI · UNIVERSITY OF WASHINGTON · PI ALEXANDER P REINER · 2020 to 2026
$5.7MGenome-Wide Dissection of Mendelian Susceptibility to Mycobacterial DiseaseR01AI095983 · NIAID · ROCKEFELLER UNIVERSITY · PI BUSTAMANTE, JACINTA, CASANOVA, JEAN-LAURENT · 2021 to 2025
$2.5MSelective pressures from inherited variation impacting myeloproliferative neoplasm initiationR01CA265726 · NCI · BOSTON CHILDREN'S HOSPITAL · PI Vijay Ganesh Sankaran · 2022 to 2026
$2.5MVariant to Function Mapping of B-ALL Risk LociR01CA292941 · NCI · BOSTON CHILDREN'S HOSPITAL · PI Adam De Smith, Vijay Ganesh Sankaran · 2024 to 2026
$2.0MClonal analysis of cancer by mitochondrial DNA barcodingR33CA278393 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI SANKARAN, VIJAY GANESH, VAN GALEN, PETER · 2023 to 2025
$1.3MDeveloping HIV Resistant Hematopoietic Stem Cells through Targeted Base EditingF31AI186590 · NIAID · HARVARD UNIVERSITY · PI Samantha JOUBRAN · 2024 to 2026
$113kNCATS NIH HHS UL1 TR001866NCI NIH HHS R01 CA265726NCI NIH HHS R01 CA292941NCI NIH HHS R33 CA278393NHLBI NIH HHS R01 HL146500NIAID NIH HHS F31 AI186590NIAID NIH HHS R01 AI095983NIDDK NIH HHS R01 DK103794NIGMS NIH HHS T32 GM144273
Abstract
The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis and dysregulated B cell receptor signaling. CBL deficiency impairs humoral immunity by limiting memory B cell formation and reducing class switching and somatic hypermutation. Consequently, antigen-specific B cell generation and adaptive immune memory are disrupted, predisposing individuals to infection. Human CBL is critical for B cell development and function but redundant for T cell biology.
Indexed as
B-LymphocytesProto-Oncogene Proteins c-cblT-LymphocytesAdaptor Proteins, Signal TransducingAnimalsApoptosisCell DifferentiationHumansImmunologic MemoryMiceReceptors, Antigen, B-CellSignal TransductionAdaptor Proteins, Signal TransducingCBLB protein, humanCBL protein, humanProto-Oncogene Proteins c-cblReceptors, Antigen, B-Cell
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