Role of 2c T Cell Receptor Residues in the Binding of Self–And Allo–Major Histocompatibility Complexes

Abstract

T cell clone 2C recognizes the alloantigen Ld and the positive selecting major histocompatibility complex (MHC), Kb. To explore the molecular basis of T cell antigen receptor (TCR) binding to different peptide/MHC (pMHC) complexes, we performed alanine scanning mutagenesis of the 2C TCR. The TCR energy maps for QL9/Ld and SIYR/Kb were remarkably similar, in that 16 of 41 Vα and Vβ alanine mutants showed reduced binding to both ligands. Several TCR residues varied in the magnitude of energy contributed to binding the two ligands, indicating that there are also unique interactions. Residues in complementarity determining region 3α showed the most notable differences in binding energetics among the ligands QL9/Ld, SIYR/Kb, and the clonotypic antibody 1B2. Various lines of evidence suggest that these differences relate to the mobility of this loop and point to the key role of conformational dynamics in pMHC recognition.