Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Victor Greiff, Ulrike Menzel, Enkelejda Miho, Cédric Weber, René Riedel, Skylar Cook, Atijeh Valai, Telma Lopes, Andreas Radbruch, Thomas H. Winkler, Sai T. Reddy
Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell developmental stages and in response to antigen exposure. However, we still lack fundamental quantitative understanding of the extent to which repertoire diversity is predetermined. Therefore, we implemented a systems immunology framework for quantifying repertoire predetermination on three distinct levels: (1) B cell development (pre-B cell, naive B cell, plasma cell), (2) antigen exposure (three structurally different proteins), and (3) four antibody repertoire components (V-gene usage, clonal expansion, clonal diversity, repertoire size) extracted from antibody repertoire sequencing data (400 million reads). Across all three levels, we detected a dynamic balance of high genetic (e.g., >90% for V-gene usage and clonal expansion in naive B cells) and antigen-driven (e.g., 40% for clonal diversity in plasma cells) predetermination and stochastic variation. Our study has implications for the prediction and manipulation of humoral immunity.

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Teaser

Greiff et al. develop an integrated systems immunology approach for quantifying the extent of antibody repertoire predetermination. They find a dynamic balance of both high genetic (maximum: 99%) and antigen-driven (maximum: 40%) repertoire predetermination. The authors also uncover stochastic variation across B cell development, antigen exposure, and repertoire components (germline gene usage, clonal expansion, clonal diversity, repertoire size), which has implications for the prediction and manipulation of humoral immunity.


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