Nature cell biology · 2025
T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response.
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Scourzic Laurianne, Izzo Franco, Teater Matt, Polyzos Alexander P, Cucereavii Lucretia, Chin Christopher R, Papin Antonin, Pinto Hugo B, Mlynarczyk Coraline, Tsialta Ioanna, Xia Min, Lidoski Abigail, Myers Robert M, Israel Eva M, Venturutti Leandro, Mackay Simon P, Hoehn Kenneth B, Skoultchi Arthur I, Béguelin Wendy, Stadtfeld Matthias, Chen Zhengming, Landau Dan A, Melnick Ari M, Apostolou Effie
Аннотация
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.