T cell help transiently unlocks a high plasticity state in germinal center B cells during the humoral immune response [ActB_RNA-seq]

During cellular differentiation, phenotypic plasticity is gradually lost due to the strengthening of epigenetic barriers, although it may be re-acquired upon disease or injury. Here, we report an unprecedented physiological gain of epigenetic plasticity among mature B cells during the humoral immune response. Acquisition of plasticity was strictly dependent on T follicular helper (TFH) cells and restricted to germinal center (GC) but not activated B cells, indicating both non- and cell-autonomous contributions to this phenotype. Importantly, GC plasticity was not dependent on proliferation and could not be solely explained by the activation of MYC programs. Instead, GC plasticity was associated with the reciprocal weakening of B cell identity and the de- repression of progenitor and stem cell-like programs induced by NFκB and other signals, downstream of TFH signaling. Therefore, physiological acquisition of GC B cell plasticity is tightly controlled by the affinity maturation positive selection checkpoint. Notably, Histone 1 loss of function, which results in aberrant stem cell gene reactivation through chromatin decompaction, allowed GC B cells to bypass this gatekeeping mechanism. Finally, patients with Diffuse LargeB Cell Lymphoma (DLBCL) that enriched for GC plasticity signatures had significantly worse outcomes, implicating a role for this mechanism in immune regulation and fitness and potential relevance to lymphomagenesis.