Cbl and Cbl-b control the germinal center reaction by facilitating naive B cell antigen processing

J Exp Med. 2020 Sep 7;217(9):e20191537. doi: 10.1084/jem.20191537.

Abstract

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antibody Formation / immunology
  • Antigen Presentation / immunology*
  • Antigens, CD / metabolism
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Cell Communication / immunology
  • Endocytosis
  • Germinal Center / immunology*
  • Immunity, Humoral
  • Intestines / immunology
  • Intestines / parasitology
  • Lymphocyte Activation / immunology
  • Lysosomes / metabolism
  • Mice, Inbred C57BL
  • Mutagenesis / genetics
  • Mutation / genetics
  • Nematospiroides dubius / immunology
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Receptors, Antigen, B-Cell / immunology
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Cblb protein, mouse
  • Receptors, Antigen, B-Cell
  • Proto-Oncogene Proteins c-cbl
  • Cbl protein, mouse