BLIMP1通过调控明区到暗区转换过程中的染色质可及性来塑造生发中心B细胞的克隆多样性

Germinal center B cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably Nr4a1, are known. We reveal an unsuspected role for BLIMP1 (Prdm1)-a plasma cell determinant-as a feedback regulator of affinity maturation. Single-cell RNA and B cell receptor (BCR) sequencing showed that B cell-specific Prdm1 loss drives an exaggerated germinal center reaction with larger clones, increased somatic hypermutation and greater clonal dominance, independent of Nr4a1. Single-cell chromatin profiling with base-resolution modeling indicated that Blimp-1 represses expression of BCR-signaling genes, gating chromatin accessibility at interferon-stimulated response elements, Ets-interferon regulatory factor composite elements, nuclear factor kappa B and Oct motifs. In the absence of BLIMP1, enhanced BCR-signaling augments activities of transcription factors that promote G1-S transition during light zone (LZ) selection and fuel dark zone (DZ) expansion. Thus, BLIMP1 attenuates BCR signaling and constrains the LZ to DZ transition, fine-tuning clonal competition, thereby maintaining repertoire diversity.