Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function
| Title: | 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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| Authors: | Vatovec T.; Neehus A. L.; Jackson K. J. L.; Avery D. T.; Bagarić I.; Erazo L.; Arango-Franco C. A.; Ogishi M.; Ahmed S. F.; Cederholm A.; Russell A. J.; 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.; Catala A.; Gambineri E.; Veltroni M.; Pandiarajan V.; Aguilar Y.; Haerynck F.; Elliott M.; Turville S.; Brillot F.; Khan T.; Consonni F.; Berteloot L.; Sewell W. A.; 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 C. C.; Landegren N.; Aiuti A.; Zhang P.; Masetti R.; Huang D. T.; Ma C. S.; Casanova J. L.; Sankaran V. G.; Bustamante J.; Tangye S. G.; Bohlen J. |
| Contributors: | Vatovec, T.; Neehus, A. L.; Jackson, K. J. L.; Avery, D. T.; Bagarić, I.; Erazo, L.; Arango-Franco, C. A.; Ogishi, M.; Ahmed, S. F.; Cederholm, A.; Russell, A. J.; 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.; Catala, A.; Gambineri, E.; Veltroni, M.; Pandiarajan, V.; Aguilar, Y.; Haerynck, F.; Elliott, M.; Turville, S.; Brillot, F.; Khan, T.; Consonni, F.; Berteloot, L.; Sewell, W. A.; 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, C. C.; Landegren, N.; Aiuti, A.; Zhang, P.; Masetti, R.; Huang, D. T.; Ma, C. S.; Casanova, J. L.; Sankaran, V. G.; Bustamante, J.; Tangye, S. G.; Bohlen, J. |
| Publication Year: | 2026 |
| Collection: | IRIS Università degli Studi di Bologna (CRIS - Current Research Information System) |
| Subject Terms: | Mosaicism; Lymphocyte development; Immune tolerance; humoral immunity; bacterial infection |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| File Description: | ELETTRONICO |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/41540267; info:eu-repo/semantics/altIdentifier/wos/WOS:001661778000001; volume:27; issue:2; firstpage:308; lastpage:322; numberofpages:15; journal:NATURE IMMUNOLOGY; https://hdl.handle.net/11585/1043207 |
| DOI: | 10.1038/s41590-025-02381-7 |
| Availability: | https://hdl.handle.net/11585/1043207; https://doi.org/10.1038/s41590-025-02381-7; https://www.nature.com/articles/s41590-025-02381-7 |
| Rights: | info:eu-repo/semantics/openAccess ; license:Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY) ; license uri:iris.PUB15 |
| Accession Number: | edsbas.F7A47419 |
| Database: | BASE |