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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.

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.