The Structure of H-2Kb and Kbm8 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, Arg⁶². The altered dynamics of Arg⁶², coupled with a small rigid-body movement in the α₁ helix encompassing this residue, correlated with biased Vα usage in the B6 mice. Moreover, an analysis of all known TCR/MHC complexes reveals that Arg⁶² invariably interacts with the TCR CDR1α loop. Accordingly, Arg⁶² appears to function as a conformational switch that may govern T cell selection and protective immunity.