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

Author:

Shrock Ellen L.123ORCID,Timms Richard T.4ORCID,Kula Tomasz123ORCID,Mena Elijah L.12ORCID,West Anthony P.5ORCID,Guo Rui678ORCID,Lee I-Hsiu9ORCID,Cohen Alexander A.5ORCID,McKay Lindsay G. A.10ORCID,Bi Caihong1112,Leng Yumei12ORCID,Fujimura Eric12ORCID,Horns Felix13ORCID,Li Mamie12ORCID,Wesemann Duane R.8111214ORCID,Griffiths Anthony10ORCID,Gewurz Benjamin E.67815,Bjorkman Pamela J.5ORCID,Elledge Stephen J.12ORCID

Affiliation:

1. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

2. Division of Genetics, Department of Medicine, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.

3. Program in Biological and Biomedical Sciences, Harvard University, Boston, MA 02115, USA.

4. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.

5. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

6. Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

7. Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.

8. Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.

9. Center for Systems Biology, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

10. National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston University, Boston, MA 02118, USA.

11. Division of Allergy and Immunology, Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

12. Massachusetts Consortium on Pathogen Readiness, Boston, MA 02115, USA.

13. Department of Bioengineering, Department of Applied Physics, Chan Zuckerberg Biohub and Stanford University, Stanford, CA 94305, USA.

14. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, 02139 USA.

15. Graduate Program in Virology, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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