Invariant VD and DJ Motifs Define a Novel Class of Human Antibodies and TCRs Prototyped by antigen receptors of Dual-Expresser Lymphocytes

Abstract

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 (CARx1-4DTAMVYYFYDW), 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.