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underlying generic properties of alphabeta TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR beta-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ beta-chain was associated with distinct TCR alpha-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR alpha-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR alpha-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.","bibjson":{"author":[{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"NA","lastname":"Borg","name":"Borg NA"},{"initials":"RM","lastname":"Brennan","name":"Brennan RM"},{"initials":"FE","lastname":"Tynan","name":"Tynan FE"},{"initials":"L","lastname":"Kjer-Nielsen","name":"Kjer-Nielsen L"},{"initials":"SL","lastname":"Silins","name":"Silins SL"},{"initials":"MJ","lastname":"Bell","name":"Bell MJ"},{"initials":"JM","lastname":"Burrows","name":"Burrows JM"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"}],"identifier":[{"id":"10.4049/jimmunol.177.10.6804","type":"doi"},{"id":"17082594","type":"pubmed"}],"issue":["10"],"journal":{"iso_abbreviation":"J. 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