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 and Izzo, Franco and Teater, Matt and Polyzos, Alexander P and Cucereavii, Lucretia and Chin, Christopher R and Papin, Antonin and Pinto, Hugo B and Mlynarczyk, Coraline and Tsialta, Ioanna and Xia, Min and Lidoski, Abigail and Myers, Robert M and Israel, Eva M and Venturutti, Leandro and Mackay, Simon P and Hoehn, Kenneth B and Skoultchi, Arthur I and Béguelin, Wendy and Stadtfeld, Matthias and Chen, Zhengming and Landau, Dan A and Melnick, Ari M and Apostolou, Effie (2026) T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response. Nature Cell Biology, 28 (1). pp. 35-48. ISSN 1476-4679 (https://doi.org/10.1038/s41556-025-01833-4)

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Abstract

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 ) 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 -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. [Abstract copyright: © 2025. The Author(s), under exclusive licence to Springer Nature Limited.]

ORCID iDs

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 ORCID logoORCID: https://orcid.org/0000-0001-9533-2881, Venturutti, Leandro, Mackay, Simon P ORCID logoORCID: https://orcid.org/0000-0001-8000-6557, Hoehn, Kenneth B, Skoultchi, Arthur I, Béguelin, Wendy, Stadtfeld, Matthias, Chen, Zhengming, Landau, Dan A, Melnick, Ari M and Apostolou, Effie;
CORE (COnnecting REpositories)