B cells transition through a T cell dependent plastic state during the adaptive immune response

During the adaptive immune response, fully mature germinal center (GC) B cells manifest the unique capacity to undergo rapid multidirectional, and dramatic phenotypic shifts and evolve into diverse memory and antibody secreting cells. No other mature cell lineages are known to display such extensive phenotypic plasticity under physiological conditions. Whether this represents a form of differentiation or re-acquisition of stem-like plasticity remain unknown. Herein, we show that GC B cells undergo a transient gain of functional plasticity, which is unprecedented under physiological conditions. Strikingly, this process, which we call “anaplasis”, was spatially and temporally restricted to GC B cells receiving T cell help. Anaplasis involved partial silencing of the B cell program, the reactivation of embryonic stem cell super-enhancers and genes and was dependent on specific transcription factors. Notably, lymphoma mutations that enhance T cell help, further increased GC stem-like functionality, whereas mutations inducing chromatin plasticity bypassed the T cell requirement. Moreover, anaplasis signatures were associated with unfavorable outcome in Diffuse Large B cell lymphoma. Altogether, our findings document that differentiated cells can re-acquire stem-like plasticity under physiological conditions. This potentially harmful phenotype co-evolved with strict non-cell autonomous checkpoints linked to immunological selection processes. GC anaplasis may help to explain why most lymphoid malignancies arise from mature GC B cells and is potentially hijacked, leading to aggressive diseases and highly fit lymphomas. Overall design: Splenic B cells from mice immunized with SRBC for 9 days were pre-enriched for B220pos cells by negative magnetic enrichment and stained for GC markers as described above before flow sorting. GC Myc-GFPpos and Myc-GFPneg fractions were sorted from 6 individual 3-month-old male mice and pooled before processing for Multiomic sequencing using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit (10X Genomics #N-1000283) according to the provider specifications. gDNA and cDNA Indexed libraries were quantified using Qubit and QC using Agilent Bioanalyzer 2100. Libraries were diluted to 2 nM and clustered on an Illumina NovaSeq 6000