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

Xin Li, Adeline Gadzinsky, Liying Gong, Haijun Tong, Virginie Calderon, Yue Li, Daisuke Kitamura, Ulf Klein, Wallace Y. Langdon, Fajian Hou, Yong Rui Zou, Hua Gu

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22 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)530-541
JournalImmunity
Volume48
Issue number3
DOIs
Publication statusPublished - 20 Mar 2018

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    Li, X., Gadzinsky, A., Gong, L., Tong, H., Calderon, V., Li, Y., Kitamura, D., Klein, U., Langdon, W. Y., Hou, F., Zou, Y. R., & Gu, H. (2018). Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction. Immunity, 48(3), 530-541. https://doi.org/10.1016/j.immuni.2018.03.006