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I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA-B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences.","bibjson":{"author":[{"initials":"MJ","lastname":"Rist","name":"Rist MJ"},{"initials":"A","lastname":"Theodossis","name":"Theodossis A"},{"initials":"NP","lastname":"Croft","name":"Croft NP"},{"initials":"MA","lastname":"Neller","name":"Neller MA"},{"initials":"A","lastname":"Welland","name":"Welland A"},{"initials":"Z","lastname":"Chen","name":"Chen Z"},{"initials":"LC","lastname":"Sullivan","name":"Sullivan LC"},{"initials":"JM","lastname":"Burrows","name":"Burrows JM"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"RM","lastname":"Brennan","name":"Brennan RM"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"R","lastname":"Khanna","name":"Khanna R"},{"initials":"AG","lastname":"Brooks","name":"Brooks AG"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"SR","lastname":"Burrows","name":"Burrows SR"}],"identifier":[{"id":"10.4049/jimmunol.1300292","type":"doi"},{"id":"23749632","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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