The Structure of H-2K super(b) and K super(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 super(bm8) compared with H-2 super(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 super(b) and K super(bm8), in complex with cognate peptide Ag. Although K super(b) and K super(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 super(62). The altered dynamics of Arg super(62), coupled with a small rigid-body movement in the alpha sub(1) helix encompassing this residue, correlated with biased V alpha usage in the B6 mice. Moreover, an analysis of all known TCR/MHC complexes reveals that Arg super(62) invariably interacts with the TCR CDR1 alpha loop. Accordingly, Arg super(62) appears to function as a conformational switch that may govern T cell selection and protective immunity.