BLIMP1 shapes germinal center B cell clonal diversity by gating chromatin accessibility during light-to-dark zone transition

Abstract

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. Singh and colleagues identify a role for the transcription factor BLIMP1, encoded by Prdm1, in the regulation of germinal center responses. They show that BLIMP1 acts as a negative feedback regulator of B cell affinity maturation and clonal dominance.