The Physiological Landscape and Specificity of Antibody Repertoires

Csepregi, L.; Hoehn, K. B.; Neumeier, D.; Taft, J. M.; Friedensohn, S.; Weber, C. R.; Kummer, A.; Sesterhenn, F.; Correia, B. E.; Reddy, S. T.

doi:10.1101/2021.09.15.460420

bioRxiv · 10.1101/2021.09.15.460420

The Physiological Landscape and Specificity of Antibody Repertoires

Csepregi, L.·Hoehn, K. B.·Neumeier, D.·Taft, J. M.·Friedensohn, S.·Weber, C. R.·Kummer, A.·Sesterhenn, F.·Correia, B. E.·Reddy, S. T.

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Abstract

Diverse antibody repertoires spanning multiple lymphoid organs (e.g., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response, remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice, and discovered that organ-specific antibody repertoire features (e.g., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen-specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.

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Csepregi, L., Hoehn, K. B., Neumeier, D., Taft, J. M., Friedensohn, S., Weber, C. R., Kummer, A., Sesterhenn, F., Correia, B. E., Reddy, S. T.. 2021-09-17. The Physiological Landscape and Specificity of Antibody Repertoires. https://doi.org/10.1101/2021.09.15.460420

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