LAUSR

&NA; 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. Graphical Abstract Figure. No caption available. HighlightsDeletion of Cbl ubiquitin ligases in GC B cells abolishes antibody affinity maturationCbls control the clonal expansion of high‐ but not low‐affinity B cells in GCsCbls prevent early exit of B cells from GC by promoting Irf4 ubiquitinationStrong CD40 and BCR signals trigger degradation of Cbls in LZ B cells, promoting GC exit &NA; 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.