Journal
IMMUNITY
Volume 48, Issue 3, Pages 530-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2018.03.006
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Funding
- Canadian Institute of Health Research [MOP142279]
- A. Aisenstadt Chair Fund
- Chinese Scholarship Council PhD training grants
- National Cancer Institute of the National Institutes of Health [R21 CA175461]
- National Health and Medical Research grant [1101318]
- Chinese Academy of Sciences/State Administration of Foreign Experts Affairs (CAS/SAFEA)
- Feinstein Institute for Medical Research
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Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in anti-body 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.
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