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Regulation of the Germinal Center Reaction and Somatic Hypermutation Dynamics by Homologous Recombination

Gianna Hirth,C. Svensson,Katrin Böttcher,S. Ullrich,M. Figge,B. Jungnickel

Published 2019 in Journal of Immunology

ABSTRACT

Key Points HR supports germinal center B cell survival and Ab affinity maturation. HR is active at the hypermutating Ig locus and influences the SHM mutation pattern. The magnitude of A:T mutagenesis during SHM of the Ig V region increases over time. Visual Abstract During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell–specific inactivation of the critical HR factor Brca2, we detected decreased proliferation, survival, and thereby class switching of ex vivo–activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in Brca2-deficient mice. These mutation pattern changes in Brca2-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.

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