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

Yeh, C.-H.; Shenkerman, N.; Song, S.; Kirshner, H.; Watanabe, A.; Liao, D.; Liang, X.; Zhang, W.; Wiehe, K.; Kelsoe, G.; Kuraoka, M.

doi:10.64898/2026.09.10.750694

bioRxiv · 10.64898/2026.09.10.750694

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

Yeh, C.-H.·Shenkerman, N.·Song, S.·Kirshner, H.·Watanabe, A.·Liao, D.·Liang, X.·Zhang, W.·Wiehe, K.·Kelsoe, G.·Kuraoka, M.

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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.

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Yeh, C.-H., Shenkerman, N., Song, S., Kirshner, H., Watanabe, A., Liao, D., Liang, X., Zhang, W., Wiehe, K., Kelsoe, G., Kuraoka, M.. 2026-09-16. Apoptotic Quality Control of Cellular Competence Limits Cryptic Germinal Center B Cell States. https://doi.org/10.64898/2026.09.10.750694

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