Work

Viral infection tunes B cell receptor copy number 2258730

Year: 2026

Type: article

Abstract: Introduction The multivalent structures of membrane-bound and soluble immunoglobulins enable germline recognition of cognate antigen despite typically low-affinity binding. Avidity, the combined strength of multiple antigen:receptor interactions, enables an increase in apparent affinity by decreasing the antigen dissociation rate. B cell receptor (BCR) affinity for antigen is modulated by somatic hypermutation and affinity maturation; however, it is unclear how apparent affinity resulting from the avidity effect is regulated and what the consequences for humoral immunity are. Herein, we investigate how viral infection modulates B cell receptor copy number to regulate antigen recognition. Methods We engineered novel structure-based probes to count the number of antigen binding sites on mouse and human B lymphocytes. These probes consist of a kappa light chain specific nanobody (VHH) with a c-terminal avi-tag for site specific biotinylation. The biotinylated VHH is then conjugated to a monomeric streptavidin (mSA) labeled with one molecule of AlexaFluor488 (AF488) to produce VHH-mSA-AF488. In flow cytometry, we deploy commercial bead standards to interpolate molecular copy number from the MFI of B cell-bound VHH-mSA-AF488. Results Following influenza virus infection in mice, naïve BCR copy number increases on all B cells, both within the bone marrow and peripheral secondary lymphoid organs. Likewise, we show that the human naïve B cell repertoire increases antigen receptor density during COVID and then returns to baseline during convalescence. Kinetically, we find that higher BCR copy number provides a cellular avidity effect that lowers the threshold for receptor activation. Conclusion Collectively, our results define a process whereby the resting BCR is modulated at the germline repertoire level to maximize responsiveness to antigen. Funding Source F31AI186217 Topic Categories Viral Immunology (VIR)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkag141.618