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<p>Germinal center B cell responses are defined by many positive regulators of affinity maturation, but few components that restrain clonal dominance, notably <i>Nr4a1</i>, are known. We reveal an unsuspected role for BLIMP1 (<i>Prdm1</i>)—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 <i>Prdm1</i> loss drives an exaggerated germinal center reaction with larger clones, increased somatic hypermutation and greater clonal dominance, independent of <i>Nr4a1</i>. 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Godhev Kumar Manakkat Vijay,
  • Bala Ramaswami,
  • Steven Gierlack,
  • Nicholas A. Pease,
  • Peter Gerges,
  • Dianyu Chen,
  • Kairavee Thakkar,
  • Luis Mena Hernandez,
  • Swapnil Keshari,
  • Heping Xu,
  • Nathan Salomonis,
  • Jishnu Das,
  • David M. Rothstein,
  • Harinder Singh

摘要

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.