THE PRESUMPTIVE CDR3 REGIONS OF BOTH T-CELL RECEPTOR ALPHA-CHAIN AND BETA-CHAIN DETERMINE T-CELL SPECIFICITY FOR MYOGLOBIN PEPTIDES

The T cell receptor α/β (TCR-a/O) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-α/β are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-α/β V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed ofTCR Vα and Vβ segments, primarily contact residues of the MHC α helices, whereas V/Jα and V/D/Jβ junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity ofantigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR α and β chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR α chains without foreknowledge of the Vα segments they utilize. © 1990, Rockefeller University Press., All rights reserved.