Document Type
Article
Publication Date
2-1-2026
Original Citation
Vatovec T,
Neehus A,
Jackson K,
Avery D,
Bagarić I,
Erazo L,
Arango-Franco C,
Ogishi M,
Ahmed S,
Cederholm A,
Russell A,
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,
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,
Landegren N,
Aiuti A,
Zhang P,
Masetti R,
Huang D,
Ma C,
Casanova J,
Sankaran V,
Bustamante J,
Tangye S,
Bohlen J.
Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function. Nat Immunol. 2026;27(2):308–22
Keywords
JGM, Humans, Proto-Oncogene Proteins c-cbl, T-Lymphocytes, B-Lymphocytes, Immunologic Memory, Signal Transduction, Cell Differentiation, Leukocytes, Animals, Receptors, Antigen, B-Cell, Immunity, Humoral, Female, Mice, Male
JAX Source
Nat Immunol. 2026;27(2):308–22
ISSN
1529-2916
PMID
41540267
DOI
https://doi.org/10.1038/s41590-025-02381-7
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.
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This work is licensed under a Creative Commons Attribution 4.0 International License.