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Cell Mol Immunol. 2019 Jan;16(1):53-64. doi: 10.1038/cmi.2017.117. Epub 2017 Dec 4.

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

Author information

1
Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA.
2
Department of Molecular Medicine, The Scripps Research Institute, 92037, La Jolla, CA, USA.
3
California Institute for Biomedical Research, 92037, La Jolla, CA, USA.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 92037, La Jolla, CA, USA.
5
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 66506, Manhattan, KS, USA.
6
IMGT, the International ImMunoGeneTics information system, Laboratoire d'ImmunoGénétique Moléculaire, Institut de Génétique Humaine, CNRS, University of Montpellier, 34396, Montpellier, France.
7
Comparative Immunogenetics Laboratory, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA. mcriscitiello@cvm.tamu.edu.
8
Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, 77807, Bryan, TX, USA. mcriscitiello@cvm.tamu.edu.
9
Department of Molecular Medicine, The Scripps Research Institute, 92037, La Jolla, CA, USA. mcriscitiello@cvm.tamu.edu.
10
Fabrus, Inc., 92037, La Jolla, CA, USA. mcriscitiello@cvm.tamu.edu.

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.

PMID:
29200193
PMCID:
PMC6318308
DOI:
10.1038/cmi.2017.117

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