A Role for Differential Variable Gene Pairing in Creating T Cell Receptors Specific for Unique Major Histocompatibility Ligands

A limited set of T cell receptor (TCR) variable (V) gene segments are used to create a repertoire of TCRs that recognize all major histocompatibility complex (MHC) ligands within a species. How individual αβTCRs are constructed to specifically recognize a limited set of MHC ligands is unclear. Here we have identified a role for the differential pairing of particular V gene segments in creating TCRs that recognized MHC class II ligands exclusively, or cross-reacted with classical and nonclassical MHC class I ligands. Biophysical and structural experiments indicated that TCR specificity for MHC ligands is not driven by germline-encoded pairwise interactions. Rather, identical TCRβ chains can have altered peptide-MHC (pMHC) binding modes when paired with different TCRα chains. The ability of TCR chain pairing to modify how V region residues interact with pMHC helps to explain how the same V genes are used to create TCRs specific for unique MHC ligands. ► MHCII-reactive TCRs can cross-react with classical and nonclassical MHCI ligands ► Specific and cross-reactive TCRs bind MHCII with a conventional footprint ► MHC-specific TCRs utilize divergent interactions to bind the same pMHC complexes ► Differential αβTCR chain pairing can result in modified TCRβ-pMHC binding