Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging

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SUMMARYAdaptive immunity involves the development of bespoke antibodies in germinal centers (GCs) through immunoglobulin somatic hypermutation (SHM) in GC dark zones (DZs) and clonal selection in light zones (LZs). Accurate selection requires that cells fully replace surface B cell receptors (BCRs) following SHM, but whether this happens before LZ entry is not clear. We found that most GC B cells degrade pre-SHM receptors before leaving the DZ, and that B cells acquiring crippling mutations during SHM rarely reached the LZ. Instead, apoptosis was triggered preferentially in late G1, a stage wherein cells with functional BCRs re-entered cell cycle or reduced surface expression of the chemokine receptor CXCR4 to enable LZ migration. Ectopic expression of the anti-apoptotic gene Bcl2 was not sufficient for cells with damaging mutations to reach the LZ, suggesting that BCR-dependent cues may actively facilitate the transition. Thus, BCR replacement and pre-screening in DZs prevents the accumulation of clones with non-functional receptors and facilitates selection in the LZ.Graphical AbstractHIGHLIGHTSGC B cells exchange surface BCRs in dark zones (DZ) following somatic hypermutationGC B cells acquiring damaging BCR mutations genes rarely transition to the light zone (LZ)Apoptosis of GC B cells in DZ occurs preferentially in the late G1 stage of cell cycleEctopic expression of Bcl2 fails to rescue LZ entry by B cells with damaged BCRsSomatic hypermutation is important for the generation of high-affinity antibodies, but this mutational process is also likely to negatively impact the functional integrity of B cell receptors (BCRs). Stewart et al. find that germinal center B cells replace surface BCRs in dark zones (DZ) and present evidence for a DZ checkpoint that prevents the accumulation of clones with non-functional BCRs, thus facilitating selection in the LZ.

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