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

Xin Li; Liying Gong; Alexandre P Meli; Danielle Karo-Atar; Weili Sun; Yongrui Zou; Irah L King; Hua Gu

doi:10.1084/jem.20191537

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.

Authors

Xin Li^{1

2}, Liying Gong^{1

3}, Alexandre P Meli⁴, Danielle Karo-Atar⁴, Weili Sun^{1

3}, Yongrui Zou⁵, Irah L King⁴, Hua Gu^{1

2

3}

Affiliations

¹ Montreal Clinical Research Institute, Montreal, Quebec, Canada.
² Department of Microbiology and Immunology, Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada.
³ Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
⁴ Department of Microbiology and Immunology, Meakins-Christie Laboratories, McGill University Health Center, Montreal, Quebec, Canada.
⁵ The Feinstein Institute for Medical Research, Manhasset, New York, NY.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding