1. Invariant VD and DJ Motifs Define a Novel Class of Human Antibodies and TCRs Prototyped by antigen receptors of Dual-Expresser Lymphocytes.
- Author
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Majety N, Ahmed R, Al-Hallaf R, Paul P, Giwa A, Heinemann J, Agha Z, Choong C, Donner T, Jie C, and Hamad ARA
- Subjects
- Humans, Complementarity Determining Regions genetics, Complementarity Determining Regions immunology, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 genetics, Computational Biology methods, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell metabolism, Amino Acid Motifs, Immunoglobulin M immunology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell, alpha-beta metabolism, Amino Acid Sequence, Antibodies, Monoclonal immunology
- Abstract
Introduction: Dual-expressing lymphocytes (DEs) are unique immune cells that express both B cell receptors (BCRs, surface antibody) and T cell receptors (TCRs). In type 1 diabetes, DE antibodies are predominated by one antibody (x-mAb), an IgM monoclonal antibody with a germline-encoded CDR3 that recognizes self-reactive TCRs. We explored if x-mAb and its interacting TCRs have distinct structural features., Methods: Using bioinformatics, we compared x-mAb and its most common interacting TCRαβ to billions of antigen receptor sequences to determine if they were unique or randomly generated., Results: X-mAb represents a unique class of human antibodies with a conserved CDR3 sequence (CARx
1-4 DTAMVYYFYDW), consisting of a fixed DJH motif (DTAMVYYFDYW) paired with various VH genes. A public TCRβ clonotype (CASSPGTEAFF) associated with x-mAb on DEs features two invariant segments, VβD (CASSPGT) and DJβ (PGTEAFF), key to two large families of public TCRβ clonotypes-CASSPGT-Jβx and CASSPGT-Jβx-formed by recombining the VβD motif with Jβ genes and the DJβ motif with Vβ genes. B cells also use CASSPGT as a VHD motif for public IGH clonotypes (CASSPGT-Jβx)., Discussion: DEs, unlike conventional T and B cells, use invariant motifs to create public antibodies and TCRs, a trait previously seen only in cartilaginous fish.- Published
- 2024
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