title: HLA peptide length preferences control CD8+ T cell responses.
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.
authors.affiliation: Centre for Immunotherapy and Vaccine Development, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Rist
authors.forename: Alex
authors.initials: A
authors.lastname: Theodossis
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Croft
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Neller
authors.forename: Andrew
authors.initials: A
authors.lastname: Welland
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Sullivan
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Burrows
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: Brennan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Brooks
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
mesh_terms: D001666:Binding Sites, Antibody; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D059911:HLA-B18 Antigen / Q000235:genetics / Q000276:immunology*; D059948:HLA-B44 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D015534:Trans-Activators / Q000276:immunology
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D018984:Epitopes, T-Lymphocyte; C495439:HLA-B*44:03 antigen; D059911:HLA-B18 Antigen; D059948:HLA-B44 Antigen; D010446:Peptide Fragments; D015534:Trans-Activators