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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^1,2

Andrew I. Webb^3,*, Natalie A. Borg^3,*, Michelle A. Dunstone^*, Lars Kjer-Nielsen, Travis Beddoe^*, James McCluskey^,, Francis R. Carbone^,, Stephen P. Bottomley^*, Marie-Isabel Aguilar^*, Anthony W. Purcell^4,5,, and Jamie Rossjohn^4,5,*

^* Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, and Department of Microbiology and Immunology, and ImmunoID, University of Melbourne, Parkville, Victoria, Australia

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 ₁ helix encompassing this residue, correlated with biased V usage in the B6 mice. Moreover, an analysis of all known TCR/MHC complexes reveals that Arg⁶² invariably interacts with the TCR CDR1 loop. Accordingly, Arg⁶² appears to function as a conformational switch that may govern T cell selection and protective immunity.

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