Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution

Major histocompatibility complex (MHC) class I variants H-2K^b and H-2K^bm8 differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B_498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against K^b-HSV8 cannot recognize H-2K^bm8-HSV8. However, substitution of Ser ^P2 to Glu^P2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2K^bm8-H2E was recognized whereas H-2K^b-H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.