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.
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.
Webb
Andrew I
AI
Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Borg
Natalie A
NA
Dunstone
Michelle A
MA
Kjer-Nielsen
Lars
L
Beddoe
Travis
T
McCluskey
James
J
Carbone
Francis R
FR
Bottomley
Stephen P
SP
Aguilar
Marie-Isabel
MI
Purcell
Anthony W
AW
Rossjohn
Jamie
J
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
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D010446:Peptide Fragments; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus