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

Vatovec, T.; Neehus, A. -L.; Jackson, K. J. L.; Avery, D. T.; Bagaric, 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.; Soudee, C.; Delabesse, E.; Goulvestre, C.; Shahrooei, M.; Puel, A.; Andre, I.; Bole-Feysot, C.; Abel, L.; Erlacher, M.; Beziat, 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.; C. S., Ma; Casanova, J. -L.; Sankaran, V. G.; Bustamante, J.; Tangye, S. G.; Bohlen, J.

doi:10.1038/s41590-025-02381-7

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.

Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function / Vatovec, T.; Neehus, A. -L.; Jackson, K. J. L.; Avery, D. T.; Bagaric, 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.; Soudee, C.; Delabesse, E.; Goulvestre, C.; Shahrooei, M.; Puel, A.; Andre, I.; Bole-Feysot, C.; Abel, L.; Erlacher, M.; Beziat, 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.. - In: NATURE IMMUNOLOGY. - ISSN 1529-2908. - 27:2(2026), pp. 308-322. [10.1038/s41590-025-02381-7]