The Physiological Landscape and Specificity of Antibody Repertoires

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.

Reference-based comparison of adaptive immune receptor repertoires

“…Specifically, our finding—that repertoire similarity does not differ across immune states—is strictly only valid for unsorted PBMC TCR repertoire data as examined in this study. As known from previous studies ( Amoriello et al., 2020 , 2021 ; Csepregi et al., 2021 ; Ghraichy et al., 2021 ; Greiff et al., 2017b ; Li et al., 2020 ; Ota et al., 2022 ; Riedel et al., 2020 ; Rosati et al., 2021 ), different cell populations (in different lymphoid organs) may behave in a highly different manner ( Figure S5 ). On the other hand, it did not escape our attention that this broad similarity in human blood samples might suggest the maintenance of lymphocyte homeostasis even in the event of chronic disease.…”

Antibodies, repertoires and microdevices in antibody discovery and characterization

“…Various organs, such as the spleen, lymph nodes, bone marrow, and blood, can be accessed, each displaying differences in antibody repertoire present in ASCs and MCs. [34][35][36] The quantity and quality of the induced repertoire in immunized animals highly depend on factors such as the chosen immunization protein (antigen), its quality, dose, administration, mouse strain, genetic model, harvest time, and immunization scheme, necessitating optimization for efficient and optimal screening 37,38 (unpublished data), but the frequency of antigen specificity in total cells is usually higher than in humans. Nevertheless, appropriately chosen conditions can lead to identifying high-affinity antibodies, as the affinity distribution tends to follow a normal distribution with outliers in the highaffinity range.…”

Complex Physical Properties of an Adaptive, Self-Organizing Biological System

“…These events can be monitored by biological techniques that assess the breadth and depth of the immune repertoire on the level of protein sequences [8][9][10][11][12][13], and various models are used for the analysis and interpretation of the observations [14][15][16][17][18]. Few models exist however that employ universal, statistical physical approaches to the system [19,20].…”