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

Abstract

Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell develop- mental stages and in response to antigen exposure. However,westilllackfundamentalquantitativeunder- standing of the extent to which repertoire diversity is predetermined. Therefore, we implemented a sys- tems immunology framework for quantifying reper- toire 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)fourantibodyrepertoirecomponents (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 sto- chastic variation. Our study has implications for the prediction and manipulation of humoral immunity.