T cell help transiently unlocks a high plasticity state in germinal center B cells during the humoral immune response [Foxo1_RNA-seq]

Germinal Center (GC) B cellsconstitutekey effectorsofthehumoral immune responseandundergoiterativerounds ofproliferation, somatic hypermutationof their immunoglobulin genesand eventuallycompete for T follicular helper (TFH) cellshelpin order togenerate cells with high affinity B cell receptor (BCR).While selected cells passing the critical TFHfitness checkpointcan differentiate toplasma cells,memory B cellsor go through additional rounds of proliferation and mutagenesis, the mechanisms enabling fully differentiated GCs to re-acquire plasticity–usually lost upon cell fate specification–arestill largely unknown.Herein,we report that matureGCsundergo a physiologicaltransientstate characterized byanincreased functional plasticity andinduced pluripotent stem cell (iPSC)reprogramming capacity.This transition state isreminiscent of anaplasisdue to theconcomitantpartial activation of embryonic stem cellandattenuation of the B cell programs.We furthermore demonstrate thatGC anaplasisis dependent on TFHcells sincein vivointerference of TFH:GC B cells communication or lymphoma driver mutationsaffectingGCsresponse to TFHcell help were shown to modulate their reprogramming efficiency accordingly. Importantly, GC stem-like gene signatures, as revealed by single-cell Multiome analysis of thistransient anaplastic state, were often enriched inDiffuse Large B cell lymphoma (DLBCL)patients and associate with poor outcomes, suggesting that this rare preexisting plastic state might be hijacked and further enhancefitnessduring lymphomagenesis.