HLA peptide length preferences control CD8+ T cell responses

Melissa J Rist, Alexander Theodossis, Nathan Paul Croft, Michelle A Neller, Andrew David Welland, Zhenjun Chen, Lucy C Sullivan, Jacqueline M Burrows, John J Miles, Rebekah M Brennan, Stephanie Gras, Rajiv Khanna, Andrew Brooks, James McCluskey, Anthony Wayne Purcell, Jamie Rossjohn, Scott R Burrows

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35 Citations (Scopus)

Abstract

Class 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.
Original languageEnglish
Pages (from-to)561-571
Number of pages11
JournalJournal of Immunology
Volume191
Issue number2
DOIs
Publication statusPublished - 2013

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