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Specificity mapping of human anti-T cell receptor monoclonal natural antibodies: defining the properties of epitope recognition promiscuity

IAN F. ROBEY, ALLEN B. EDMUNDSON^*, SAMUEL F. SCHLUTER, DAVID E. YOCUM and JOHN J. MARCHALONIS¹

Department of Microbiology and Immunology; and the
Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, Arizona, USA; and
^* Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

¹Correspondence: Department of Microbiology and Immunology; and the Arizona Arthritis Center, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.

The classical concept of antibody binding is defined as an exclusive and high-affinity interaction with one epitope. The emerging reality about antibody combing sites, however, is that some can bind unrelated determinants. The studies presented here define this quality as epitope recognition promiscuity by analyzing the capacity of monoclonal human autoantibodies to bind sets of overlapping peptides duplicating the complete structures of T cell receptor (TCR) and ß chains and immunoglobulin chain. We assessed the binding of these monoclonal antibodies (mAbs) to a set of homologous peptides corresponding to the CDR1 segments of human Vß gene products, a major epitope used in the selection of the antibodies. We present data on the binding characteristics of four human mAbs selected for the ability to bind TCR epitopes. These mAbs are IgM molecules with V_H and V_L sequences in germline configuration, but have diverse V_H CDR3 regions. These studies aim to characterize the property of epitope promiscuity and show that the relationship between the binding site and its epitope is a complex interaction and unpredictable from antigen sequence alone. Our results support the conclusion that epitope recognition promiscuity is a genuine feature of antibody and TCR recognition.—Robey, I. F., Edmundson, A. B., Schluter, S. F., Yocum, D. E., Marchalonis, J. J. Specificity mapping of human anti-T cell receptor monoclonal natural antibodies: defining the properties of epitope recognition promiscuity.

Key Words: antigen binding site • polyreactivity • mAbs • affinity