Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction

Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we f...

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Published in:Immunity (Cambridge, Mass.) Mass.), 2018-03, Vol.48 (3), p.530-541.e6
Main Authors: Li, Xin, Gadzinsky, Adeline, Gong, Liying, Tong, Haijun, Calderon, Virginie, Li, Yue, Kitamura, Daisuke, Klein, Ulf, Langdon, Wallace Y., Hou, Fajian, Zou, Yong-Rui, Gu, Hua
Format: Article
Language:English
Subjects:
Affinity
Animals
Antibody Affinity - ethics
Antibody Affinity - immunology
antibody affinity maturation
Antibody Formation - genetics
Antibody Formation - immunology
Antigens
B cell
B-Lymphocyte Subsets - immunology
B-Lymphocyte Subsets - metabolism
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Cbl ubiquitin ligase
Cbl-b protein
CD40 antigen
Cell Differentiation - genetics
Cell Differentiation - immunology
Clonal Selection, Antigen-Mediated - genetics
Clonal Selection, Antigen-Mediated - immunology
Degradation
Expansion
Gene Expression
Gene Knockout Techniques
Germinal center
Germinal Center - immunology
Germinal Center - metabolism
Germinal centers
Immunoglobulins
Immunological memory
Interferon regulatory factor 4
Interferon Regulatory Factors - genetics
Interferon Regulatory Factors - metabolism
Irf4
Kinases
Lymphocyte Activation - genetics
Lymphocyte Activation - immunology
Lymphocyte receptors
Lymphocytes B
Medical research
Memory cells
Mice
Mice, Transgenic
Mutation
Plasma cells
Protein Binding
Proteins
Proteolysis
Proto-Oncogene Proteins c-cbl - genetics
Proto-Oncogene Proteins c-cbl - metabolism
Receptors, Antigen, B-Cell - genetics
Receptors, Antigen, B-Cell - metabolism
T cell receptors
Transcription factors
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary:Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we found that deleting E3 ubiquitin ligases Cbl and Cbl-b (Cbls) in GC B cells resulted in the early exit of high-affinity antigen-specific B cells from the GC reaction and thus impaired clonal expansion. Cbls were highly expressed in GC light zone (LZ) B cells, where they promoted the ubiquitination and degradation of Irf4, a transcription factor facilitating PC fate choice. Strong CD40 and BCR stimulation triggered the Cbl degradation, resulting in increased Irf4 expression and exit from GC affinity selection. Thus, a regulatory cascade that is centered on the Cbl ubiquitin ligases ensures affinity-driven clonal expansion by connecting BCR affinity signals with differentiation programs. [Display omitted] •Deletion of Cbl ubiquitin ligases in GC B cells abolishes antibody affinity maturation•Cbls control the clonal expansion of high- but not low-affinity B cells in GCs•Cbls prevent early exit of B cells from GC by promoting Irf4 ubiquitination•Strong CD40 and BCR signals trigger degradation of Cbls in LZ B cells, promoting GC exit Li et al. find that clonal expansion of high affinity B cells in GCs depends on the Cbl ubiquitin ligases, which prevent premature GC exit by promoting the degradation of Irf4 in light zone B cells. Strong CD40 and BCR signals trigger Cbl degradation, thus enabling GC exit.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2018.03.006