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

Abstract

Germinal center (GC) 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-seq and B cell receptor (BCR) seq showed that B cell specific Prdm1 loss drives an exaggerated GC reaction with larger clones, increased somatic hypermutation, and greater clonal dominance, independent of Nr4a1. Single cell chromatin profiling with base-resolution modeling indicated that Blimp1 represses expression of BCR-signaling genes, gating chromatin accessibility at ISRE, EICE, NFKB, 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.