Apoptotic Quality Control of Cellular Competence Limits Cryptic Germinal Center B Cell States

Abstract

Germinal center (GC) B cells undergo extensive apoptosis, but how this process shapes evolving GC populations remains unclear. Using mice lacking intrinsic apoptotic effectors BAK and BAX in B cells, we found that mitochondrial apoptosis was dispensable for affinity maturation but critical for controlling GC size and cellular composition, showing that GC population dynamics and affinity maturation can be uncoupled. BAK/BAX-deficient mice mounted enlarged and prolonged GC responses, largely due to the accumulation of non-proliferating Ki-67loCD71lo dark zone (DZ) B cells. CD71hi and CD71lo DZ cells exhibited similar B-cell receptor (BCR) avidity, retained potential for proliferation and plasmacytic differentiation, and shared clonal lineages, indicating recurrent emergence of non-proliferating DZ populations. A subset also carried Somatic-hypermutation-derived defects that abolished antibody expression despite apparently productive V(D)J sequences; reversion of a single amino acid substitution often restored expression. Mitochondrial apoptosis thus enforces cellular quality control in the GC by limiting the persistence of non-proliferating and expression-defective states while remaining dispensable for affinity maturation.