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Immunogenetic factors driving formation of ultralong VH CDR3 in Bos taurus antibodies

Cellular & Molecular Immunology volume 16, pages 53–64 (2019)Cite this article

Abstract

The antibody repertoire of Bos taurus is characterized by a subset of variable heavy (VH) chain regions with ultralong third complementarity determining regions (CDR3) which, compared to other species, can provide a potent response to challenging antigens like HIV env. These unusual CDR3 can range to over seventy highly diverse amino acids in length and form unique β-ribbon ‘stalk’ and disulfide bonded ‘knob’ structures, far from the typical antigen binding site. The genetic components and processes for forming these unusual cattle antibody VH CDR3 are not well understood. Here we analyze sequences of Bos taurus antibody VH domains and find that the subset with ultralong CDR3 exclusively uses a single variable gene, IGHV1-7 (VHBUL) rearranged to the longest diversity gene, IGHD8-2. An eight nucleotide duplication at the 3′ end of IGHV1-7 encodes a longer V-region producing an extended F β-strand that contributes to the stalk in a rearranged CDR3. A low amino acid variability was observed in CDR1 and CDR2, suggesting that antigen binding for this subset most likely only depends on the CDR3. Importantly a novel, potentially AID mediated, deletional diversification mechanism of the B. taurus VH ultralong CDR3 knob was discovered, in which interior codons of the IGHD8-2 region are removed while maintaining integral structural components of the knob and descending strand of the stalk in place. These deletions serve to further diversify cysteine positions, and thus disulfide bonded loops. Hence, both germline and somatic genetic factors and processes appear to be involved in diversification of this structurally unusual cattle VH ultralong CDR3 repertoire.

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Acknowledgements

This work was supported by NIH grant R01 GM105826-01 to VVS, R21 AI120791 to VVS, WM and MFC and NSF grant #IOS1257829 to MFC. AT is supported by Scripps Genomic Medicine, an NIH-NCATS Clinical and Translational Science Award (CTSA; 5 UL1 RR025774).

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Authors and Affiliations

  1. Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA

    Thaddeus C Deiss, Patricia L Chen & Michael F Criscitiello

  2. Department of Molecular Medicine, The Scripps Research Institute, 92037, La Jolla, CA, USA

    Melissa Vadnais & Vaughn V Smider

  3. California Institute for Biomedical Research, 92037, La Jolla, CA, USA

    Feng Wang

  4. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 92037, La Jolla, CA, USA

    Ali Torkamani

  5. Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 66506, Manhattan, KS, USA

    Waithaka Mwangi

  6. IMGT, the International ImMunoGeneTics information system, Laboratoire d’ImmunoGénétique Moléculaire, Institut de Génétique Humaine, CNRS, University of Montpellier, 34396, Montpellier, France

    Marie-Paule Lefranc

  7. Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, 77807, Bryan, TX, USA

    Michael F Criscitiello

  8. Fabrus, Inc., 92037, La Jolla, CA, USA

    Vaughn V Smider

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  1. Thaddeus C Deiss
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  2. Melissa Vadnais
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Correspondence to Michael F Criscitiello or Vaughn V Smider.

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Deiss, T., Vadnais, M., Wang, F. et al. Immunogenetic factors driving formation of ultralong VH CDR3 in Bos taurus antibodies. Cell Mol Immunol 16, 53–64 (2019). https://doi.org/10.1038/cmi.2017.117

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