Insights from the Memory B Cell Repertoire: Molecular Motifs of Viral Reactivity

Abstract

The B cell compartment of the adaptive immune system plays a critical role in the generation of antibodies in a variety of immune settings. As humans, we experience repeated exposure to viral antigens through infection and vaccination, resulting in the generation of diverse, and largely unique, antigen-specific antibody repertoires. Despite years of antibody discovery research, however, a detailed mapping of the similarities and differences of antibody responses to different pathogens at the repertoire level is lacking. In this dissertation, using the LIBRA-seq technology, we generated a large dataset of antibody-antigen pairs against twenty viral antigens representing diverse pathogens of biomedical significance. Analysis uncovered virus-specific patterns in variable gene usage, gene pairing, somatic hypermutation, as well as the presence of convergent antiviral signatures across multiple individuals. Our results indicate that, for B cell receptors originating from different individuals but leveraging an identical combination of heavy and light chain germline genes, there is a specific CDR3 identity threshold that defines whether these B cells may share the same antigen specificity, providing experimentally grounded criteria for defining public antibody clonality. Deeper characterization of select antibodies against respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and human parainfluenza virus type 3 (hPIV3), revealed several potently neutralizing antibodies, enhancing our understanding of the sites of viral vulnerability on hPIV3 as well as our understanding of the genetic and structural determinants of cross-reactivity between RSV and hMPV. Elucidation of the fundamental rules governing antibody-antigen interactions can lead to transformative new approaches for the development of antibody therapeutics and vaccines against current and emerging viruses.