title: The structure of H-2K(b) and K(bm8) complexed to a herpes simplex virus determinant: evidence for a conformational switch that governs T cell repertoire selection and viral resistance.
abstract: Polymorphism within the MHC not only affects peptide specificity but also has a critical influence on the T cell repertoire; for example, the CD8 T cell response toward an immunodominant HSV glycoprotein B peptide is more diverse and of higher avidity in H-2(bm8) compared with H-2(b) mice. We have examined the basis for the selection of these distinct antiviral T cell repertoires by comparing the high-resolution structures of K(b) and K(bm8), in complex with cognate peptide Ag. Although K(b) and K(bm8) differ by four residues within the Ag-binding cleft, the most striking difference in the two structures was the disparate conformation adopted by the shared residue, Arg(62). The altered dynamics of Arg(62), coupled with a small rigid-body movement in the alpha(1) helix encompassing this residue, correlated with biased Valpha usage in the B6 mice. Moreover, an analysis of all known TCR/MHC complexes reveals that Arg(62) invariably interacts with the TCR CDR1alpha loop. Accordingly, Arg(62) appears to function as a conformational switch that may govern T cell selection and protective immunity.
authors.affiliation: Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Borg
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Dunstone
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.forename: Travis
authors.initials: T
authors.lastname: Beddoe
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Bottomley
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
mesh_terms: D000818:Animals; D006183:H-2 Antigens / Q000737:chemistry*; D007113:Immunity, Innate; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus