title: Structural basis for the restoration of TCR recognition of an MHC allelic variant by peptide secondary anchor substitution.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Miley
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi
authors.forename: Beatrix M
authors.initials: BM
authors.lastname: Metzner
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wu
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Zugich
authors.forename: Daved H
authors.initials: DH
authors.lastname: Fremont
mesh_terms: D000483:Alleles; D000818:Animals; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000737:chemistry*; D006860:Hydrogen Bonding; D016056:Immunodominant Epitopes; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D013601:T-Lymphocytes / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus