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. Here, by mapping 376 immunodominant “public epitopes” at high resolution and characterizing several of their cognate antibodies, we conclude 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 which, in case studies, are critical for public epitope recognition. GRAB motifs represent a fundamental component of the immune system’s architecture that ensures antibody recognition of pathogens and promotes species-specific reproducible responses that can exert selective pressure on pathogens.