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

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.