Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function

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.

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Nature Immunology
Published
2026-01-15
DOI
https://doi.org/10.1038/s41590-025-02381-7
Citations
1
Primary Topic
Ubiquitin and proteasome pathways
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article
Field-Weighted Citation Impact
22.24
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article

Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function

Francesco Baccelli, Laureline Berteloot, Z. Janda, Laëtitia Largeaud et al.
1 citations
Nature Immunology
Ubiquitin and proteasome pathways
22.24
article

Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function

Francesco Baccelli, Laureline Berteloot, Z. Janda, Laëtitia Largeaud, Lara Wahlster, Davide Leardini, Miriam Erlacher, Francesca Vendemini, Michael R. Elliott, Jessica N. Peel, Geetha Rao, Erika Della Mina, Tianyi Ye, Lucia Gabriela Ramos Erazo, Francesco Saettini, Boris Bessot, Danielle T. Avery, Isabelle André, Steicy Sobrino, Syed Feroj Ahmed, Edoardo Muratore, Carlos A. Arango-Franco, Allison Zhang, Ф. Пегораро, Samantha Joubran, Christopher C. Goodnow, Anne Puel, Yurena Aguilar, Axel Cederholm, Emmanuelle Six, Federica Barzaghi, Claire Goulvestre, Dena Al-Rifai, Jacques Dutrieux, Filippo Consonni, Emily Villalpando, Taja Vatovec, Ivan Bagarić, Peng Zhang, Chantal Lagresle-Peyrou, Hailun Li, Fabienne Brillot, Francesca Conti, Marine Michelet, Tom Le Voyer, C. Masson, Cécile Roullion, Vignesh Pandiarajan, Laia Alsina, Eleonora Gambineri, Amanda Russell, Vivien Béziat, William A. Sewell, Nils Landegren, Cindy S. Ma, Nima Parvaneh, Rowena Bull, Marinella Veltroni, Masato Ogishi, Stuart Turville, Taushif Khan, Yoann Seeleuthner, Filomeen Haerynck, Remi Cheynier, Katherine J. L. Jackson, Eric Delabesse, Nico Marr, Stuart G. Tangye, Mohammad Shahrooei, Danny T. Huang, Albert Catala, Lori Buetow, Jacinta Bustamante, Riccardo Masetti, Jean-Laurent Casanova, Christine Bole-Feysot, Jonathan Bohlen, Benedicte de Muylder
article en
1 citations

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.

Nature ImmunologyVol. 27(2)
Broad Institute (US), Uppsala University (SE), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), The University of Sydney (AU), Hospital Sant Joan de Déu Barcelona (ES), Howard Hughes Medical Institute (US), Université Toulouse III - Paul Sabatier (FR), Harvard University (US), Garvan Institute of Medical Research (AU), Vita-Salute San Raffaele University (IT), Inserm (FR), University of Freiburg (DE), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Paris Cité (FR), Heidelberg University (DE), Science for Life Laboratory (SE), Ghent University Hospital (BE), University Medical Center Freiburg (DE), Cancer Research UK (GB), Karolinska Institutet (SE), LMU Klinikum (DE), Centre Hospitalier Universitaire de Toulouse (FR), UNSW Sydney (AU), Universidad de Antioquia (CO), Hospital for Sick Children Pediatric Center (US), Centre de Recherches en Cancérologie de Toulouse (FR), Hôpital Cochin (FR), Chris O’Brien Lifehouse (AU), Assistance Publique – Hôpitaux de Paris (FR), Toulouse Mathematics Institute (FR), Azienda Ospedaliera San Gerardo (IT), Children's Medical Center (IR), Meyer Children's Hospital (IT), Hospital Universitario Miguel Servet (ES), Jackson Laboratory (US), Dana-Farber Cancer Institute (US), Azienda USL di Bologna (IT), St Vincent's Clinic (AU), Groupe Hospitalier Cochin - Port-Royal, Hôtel-Dieu, Broca - La Collégiale (FR), Sydney Institute of Marine Science (AU), Institut Cochin (FR), The San Raffaele Telethon Institute for Gene Therapy (IT), Hôpital Saint-Louis (FR), Hamad bin Khalifa University (QA), Deutsches Herzzentrum München (DE), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Ulm (DE), Human Genetic of Infectious Diseases (FR), Institut des Maladies Génétiques Imagine (FR), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University of Florence (IT), Post Graduate Institute of Medical Education and Research (IN), Tehran University of Medical Sciences (IR), Universitat de Barcelona (ES), University of Glasgow (GB), Ludwig-Maximilians-Universität München (DE), Rockefeller University (US), University of Bologna (IT)
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Ubiquitin and proteasome pathways
22.24
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