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<p>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 <i>CBL</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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

摘要

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.