Germline-encoded amino acid-binding motifs drive immunodominant public antibody responses

Despite the vast diversity of the antibody repertoire, infected individuals often mount antibody responses to precisely the same epitopes within antigens. The immunological mechanisms underpinning this phenomenon remain unknown. By mapping 376 immunodominant “public epitopes” at high resolution and characterizing several of their cognate antibodies, we concluded that germline-encoded sequences in antibodies drive recurrent recognition. Systematic analysis of antibody-antigen structures uncovered 18 human and 21 partially overlapping mouse germline-encoded amino acid–binding (GRAB) motifs within heavy and light V gene segments that in case studies proved critical for public epitope recognition. GRAB motifs represent a fundamental component of the immune system’s architecture that promotes recognition of pathogens and leads to species-specific public antibody responses that can exert selective pressure on pathogens. Description Antibodies GRAB their targets Different individuals will reproducibly generate antibodies against the same epitopes after exposure to a pathogen. However, the mechanisms driving the production of these “public antibodies” continue to be poorly understood. Shrock et al. used a phage display platform called VirScan to glean additional insights into this process. They found that many human V gene segments contained germline-encoded amino acid–binding (GRAB) motifs that bind particular amino acids and are essential for antibody recognition. Moreover, a comparison of mouse and human GRAB motifs uncovered only a partial overlap, which may explain the distinct public epitopes targeted by different species. —STS Antibody genes have GRAB motifs that bind specific amino acids and drive reproducible responses to immunodominant epitopes. INTRODUCTION Antibodies are generated by a DNA recombination mechanism occurring in the immunoglobulin heavy and light chain genes in which modular VDJ (for heavy) and VJ (for light) gene segments are combinatorially assembled. The vast complexity of the antibody repertoire allows many species to generate antibodies against virtually any protein. However, when different individuals are exposed to a given pathogen they often mount antibody responses to the same precise protein regions—or epitopes—from the pathogen. The mechanisms underlying these recurrent antibody responses to immunodominant “public epitopes” are not well understood. RATIONALE We set out to identify a collection of immunodominant public epitopes that would allow us to study mechanisms underlying recurrent antibody responses. We employed VirScan—a phage display platform programmed to display peptides covering the entire human virome—to identify the epitopes of antiviral antibodies from a large cohort of individuals in a high-throughput manner. Additionally, we isolated B cell receptors from different individuals that bound to model public epitopes in order to investigate their determinants of specificity. Finally, we performed a systematic analysis of antibody–antigen structures from the Protein Data Bank (PDB) to search for recurrent modes of antigen recognition. RESULTS We mapped 376 immunodominant public epitopes from 51 viral species to single-amino-acid resolution. Antibodies from different individuals that recognized the same public epitope often (i) shared light chain isotype (kappa or lambda) and (ii) bound the same precise critical residues in the epitope. Public epitopes showed biased amino acid composition, including a striking enrichment of lysine at the borders of public epitopes recognized by antibodies with lambda light chains. We examined 50 B cell receptors recognizing three model public epitopes in detail and observed conserved V gene segment usage but almost no conservation of heavy chain CDR3 sequences, indicating that key specificity determinants lay within the V gene segments themselves. Structural analysis of antibody–antigen complexes in the PDB uncovered 18 human V gene segments that harbor germline-encoded amino acid–binding (GRAB) motifs that specifically bind to particular amino acids. Among these were a family of six closely related lambda V gene segments with similar GRAB motifs specific for border lysines. We confirmed that the GRAB motifs we identified were critical for antibody recognition of two model public epitopes. Analysis of murine antibody–antigen structures revealed 21 V gene segment–encoded GRAB motifs that only partially overlapped with the human GRAB motifs, which may explain why there is little overlap between the public epitopes recognized across species. Thus, there appears to be a structural basis underlying the notable convergence in humoral immune responses to immunodominant public epitopes across humans and the differing public epitope selection across species. CONCLUSION Recurrent antibody responses to immunodominant public epitopes are a general feature of humoral immunity. We propose that they are driven by GRAB motifs, a germline-encoded component of the architecture of the antibody repertoire that predisposes antibodies to recognize particular structures and thus influences epitope selection and composition. Public epitopes likely arise in part because they are best aligned for recognition by GRAB motifs and can thus be bound by a relatively large precursor pool of B cells. GRAB motifs may have evolved to ensure efficient antibody responses to pathogens; the recurrent responses they engender across populations likely exert selective pressure on pathogens and influence host–pathogen coevolution. Uncovering origins of public antibody responses. VirScan reveals shared antibody responses to certain regions of viral proteins (“public epitopes”) across human populations. Heatmap color represents the strength of the antibody response in each individual (columns) to each peptide of a viral protein (rows). An analysis of antibody–antigen structures reveals that antibody genes harbor germline-encoded motifs that specifically bind certain amino acids and drive recognition of public epitopes.