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<p>During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (T<sub>FH</sub>) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other T<sub>FH</sub>-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis.</p>

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T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Laurianne Scourzic,
  • Franco Izzo,
  • Matt Teater,
  • Alexander P. Polyzos,
  • Lucretia Cucereavii,
  • Christopher R. Chin,
  • Antonin Papin,
  • Hugo B. Pinto,
  • Coraline Mlynarczyk,
  • Ioanna Tsialta,
  • Min Xia,
  • Abigail Lidoski,
  • Robert M. Myers,
  • Eva M. Israel,
  • Leandro Venturutti,
  • Simon P. Mackay,
  • Kenneth B. Hoehn,
  • Arthur I. Skoultchi,
  • Wendy Béguelin,
  • Matthias Stadtfeld,
  • Zhengming Chen,
  • Dan A. Landau,
  • Ari M. Melnick,
  • Effie Apostolou

摘要

During the germinal centre (GC) reaction, mature B cells undergo rapid and reversible phenotypic shifts that are essential for adaptive immunity. Here we report that GC B cells, unlike other mature B cells, transiently acquire a unique epigenetic plasticity, demonstrated by their enhanced capacity to reprogram to induced pluripotent stem cells. This plasticity depends on T follicular helper (TFH) cells and is not due to increased proliferation or MYC activation. Instead, it involves weakening of B-cell identity and derepression of stem and progenitor programs driven by NF-κB and other TFH-derived signals. Thus, physiological GC plasticity is tightly constrained by the affinity maturation process of positive selection. Loss of histone 1, a chromatin compaction regulator restricting the accessibility of embryonic stem cell programs, further enhances GC plasticity by bypassing this gatekeeping mechanism. Importantly, patients with B-cell lymphoma enriched for GC plasticity signatures had worse outcomes, suggesting that this mechanism may also contribute to lymphomagenesis.