αβ T Cell Receptors that Do Not Undergo Major Histocompatibility Complex-Specific Thymic Selection Possess Antibody-like Recognition Specificities

Major histocompatibility complex (MHC) restriction is the cardinal feature of T cell antigen recognition and is thought to be intrinsic to alpha beta T cell receptor (TCR) structure because of germline-encoded residues that impose MHC specificity. Here, we analyzed alpha beta TCRs from T cells that had not undergone MHC-specific thymic selection. Instead of recognizing peptide-MHC complexes, the two alpha beta TCRs studied here resembled antibodies in recognizing glycosylation-dependent conformational epitopes on a native self-protein, CD155, and they did so with high affinity independently of MHC molecules. Ligand recognition was via the alpha beta TCR combining site and involved the identical germline-encoded residues that have been thought to uniquely impose MHC specificity, demonstrating that these residues do not only promote MHC binding. This study demonstrates that, without MHC-specific thymic selection, alpha beta TCRs can resemble antibodies in recognizing conformational epitopes on MHC-independent ligands.