Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function
Por:
Vatovec T, Neehus AL, Jackson KJL, Avery DT, Bagaric I, Erazo L, Arango-Franco CA, Ogishi M, Ahmed SF, Cederholm A, Russell AJ, Della Mina E, Al-Rifai D, Bull R, Buetow L, Sobrino S, Zhang A, Wahlster L, Michelet M, Parvaneh N, Peel J, Barzaghi F, Leardini D, Philippot Q, Saettini F, Dutrieux J, de Muylder B, Vendemini F, Baccelli F, Català-Temprano A, Gambineri E, Veltroni M, Pandiarajan V, Aguilar Y, Haerynck F, Elliott M, Turville S, Brillot F, Khan T, Consonni F, Berteloot L, Sewell WA, Rao G, Largeaud L, Conti F, Roullion C, Masson C, Pegoraro F, Ye T, Joubran S, Villalpando E, Bessot B, Seeleuthner Y, Le Voyer T, Rosain J, Li H, Janda Z, Muratore E, Soudée C, Delabesse E, Goulvestre C, Shahrooei M, Puel A, André I, Bole-Feysot C, Abel L, Erlacher M, Béziat V, Lagresle-Peyrou C, Cheynier R, Six E, Marr N, Pasquet M, Alsina L, Goodnow CC, Landegren N, Aiuti A, Zhang P, Masetti R, Huang DT, Ma CS, Casanova JL, Sankaran VG, Bustamante J, Tangye SG and Bohlen J
Publicada:
1 feb 2026
Ahead of Print:
1 ene 2026
Resumen:
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.
Filiaciones:
Vatovec T:
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Heidelberg University, Heidelberg, Germany
Neehus AL:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Jackson KJL:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Avery DT:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Bagaric I:
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Heidelberg University, Heidelberg, Germany
Erazo L:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
Arango-Franco CA:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia
Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR1163, Université Paris Cité, Paris, France
Ogishi M:
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Ahmed SF:
Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
Cederholm A:
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Russell AJ:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Della Mina E:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Al-Rifai D:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Bull R:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Buetow L:
Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
Sobrino S:
Paris Cité University, Imagine Institute, Paris, France
Laboratory of Chromatin and Gene Regulation during Development, Paris Cité University, INSERM U1163, Imagine Institute, Paris, France
Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France
Zhang A:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Wahlster L:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Michelet M:
Unit of Allergy and Pneumology, Childrens Hospital, Toulouse, France
Parvaneh N:
Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
Children's Medical Center, Tehran, Iran
Peel J:
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Barzaghi F:
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Leardini D:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Philippot Q:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Saettini F:
Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Dutrieux J:
Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France
de Muylder B:
Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France
Vendemini F:
Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Baccelli F:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Català-Temprano A:
Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Gambineri E:
Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy
Veltroni M:
Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy
Pandiarajan V:
Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Aguilar Y:
Pediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain
Haerynck F:
Department of Pediatric Pulmonology, Infectious Diseases and Immunology, Ghent University Hospital, Ghent, Belgium
Primary Immunodeficiency Research Lab, Centre for Primary Immunodeficiency Ghent, Ghent University Hospital, Ghent, Belgium
Elliott M:
Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
Turville S:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Brillot F:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Khan T:
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
Department of Immunology, Sidra Medicine, Doha, Qatar
The Jackson Laboratory, Farmington, CT, USA
Consonni F:
Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy
Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
Berteloot L:
Department of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France
Sewell WA:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
Rao G:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Largeaud L:
Laboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France
Conti F:
Pediatric Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
Roullion C:
Paris Cité University, Imagine Institute, Paris, France
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris Cite University, Paris, France
Masson C:
Paris Cité University, Imagine Institute, Paris, France
Bioinformatic Plateform, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris Cite University, Paris, France
Pegoraro F:
Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy
Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
Ye T:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Joubran S:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Villalpando E:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Bessot B:
Paris Cité University, Imagine Institute, Paris, France
Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, APHP, INSERM, Paris, France
Seeleuthner Y:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Le Voyer T:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Clinical Immunology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Paris, France
Rosain J:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children AP-HP, Paris, France
Li H:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Janda Z:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Heidelberg University, Heidelberg, Germany
Muratore E:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Soudée C:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Delabesse E:
Department of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, University Paul-Sabatier Toulouse, Toulouse, France
Goulvestre C:
Laboratory of Immunology, Cochin Hospital, Paris, France
Shahrooei M:
Dr. Shahrooei Lab, Tehran, Iran
Puel A:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
André I:
Paris Cité University, Imagine Institute, Paris, France
Bole-Feysot C:
Paris Cité University, Imagine Institute, Paris, France
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris Cite University, Paris, France
Abel L:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Erlacher M:
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
Béziat V:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR1163, Université Paris Cité, Paris, France
Lagresle-Peyrou C:
Paris Cité University, Imagine Institute, Paris, France
Bioinformatic Plateform, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UAR3633, Paris Cite University, Paris, France
Cheynier R:
Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France
Six E:
Paris Cité University, Imagine Institute, Paris, France
Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France
Marr N:
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
Department of Immunology, Sidra Medicine, Doha, Qatar
Pasquet M:
Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
Alsina L:
Clinical 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
Goodnow CC:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Cellular Genomics Futures Institute & School of Biomedical Sciences, UNSW Sydney, Sydney, New South Wales, Australia
Landegren N:
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden
Aiuti A:
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
Università Vita-Salute San Raffaele, Milan, Italy
Zhang P:
Paris Cité University, Imagine Institute, Paris, France
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Masetti R:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Huang DT:
Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
School of Cancer Sciences, University of Glasgow, Glasgow, UK
Ma CS:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
Casanova JL:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Howard Hughes Medical Institute, Boston, MA, USA
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
Sankaran VG:
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Howard Hughes Medical Institute, Boston, MA, USA
Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Bustamante J:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USA
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children AP-HP, Paris, France
Tangye SG:
Garvan Institute of Medical Research, Sydney, New South Wales, Australia
School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
Bohlen J:
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Necker Branch, Inserm U1163, Paris, France
Paris Cité University, Imagine Institute, Paris, France
Department of Pediatrics, Dr. von Hauner Childrens Hospital, LMU Klinikum, Munich, Germany
German Center for Child and Adolescent Health (DZKJ), Munich Site, Munich, Germany
Green Submitted, hybrid
|