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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Rist, M. J., Theodossis, A., Croft, N. P., Neller, M. A., Welland, A. D., Chen, Z., ... Burrows, S. R. (2013). HLA peptide length preferences control CD8+ T cell responses. Journal of Immunology, 191(2), 561-571. https://doi.org/10.4049/jimmunol.1300292
Rist, Melissa J ; Theodossis, Alexander ; Croft, Nathan Paul ; Neller, Michelle A ; Welland, Andrew David ; Chen, Zhenjun ; Sullivan, Lucy C ; Burrows, Jacqueline M ; Miles, John J ; Brennan, Rebekah M ; Gras, Stephanie ; Khanna, Rajiv ; Brooks, Andrew ; McCluskey, James ; Purcell, Anthony Wayne ; Rossjohn, Jamie ; Burrows, Scott R. / HLA peptide length preferences control CD8+ T cell responses. In: Journal of Immunology. 2013 ; Vol. 191, No. 2. pp. 561-571.
@article{2ddae2304e484d71a55bf5f17c4ebe02,
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.",
author = "Rist, {Melissa J} and Alexander Theodossis and Croft, {Nathan Paul} and Neller, {Michelle A} and Welland, {Andrew David} and Zhenjun Chen and Sullivan, {Lucy C} and Burrows, {Jacqueline M} and Miles, {John J} and Brennan, {Rebekah M} and Stephanie Gras and Rajiv Khanna and Andrew Brooks and James McCluskey and Purcell, {Anthony Wayne} and Jamie Rossjohn and Burrows, {Scott R}",
year = "2013",
doi = "10.4049/jimmunol.1300292",
language = "English",
volume = "191",
pages = "561--571",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "2",

}

Rist, MJ, Theodossis, A, Croft, NP, Neller, MA, Welland, AD, Chen, Z, Sullivan, LC, Burrows, JM, Miles, JJ, Brennan, RM, Gras, S, Khanna, R, Brooks, A, McCluskey, J, Purcell, AW, Rossjohn, J & Burrows, SR 2013, 'HLA peptide length preferences control CD8+ T cell responses' Journal of Immunology, vol. 191, no. 2, pp. 561-571. https://doi.org/10.4049/jimmunol.1300292

HLA peptide length preferences control CD8+ T cell responses. / Rist, Melissa J; Theodossis, Alexander; Croft, Nathan Paul; Neller, Michelle A; Welland, Andrew David; Chen, Zhenjun; Sullivan, Lucy C; Burrows, Jacqueline M; Miles, John J; Brennan, Rebekah M; Gras, Stephanie; Khanna, Rajiv; Brooks, Andrew; McCluskey, James; Purcell, Anthony Wayne; Rossjohn, Jamie; Burrows, Scott R.

In: Journal of Immunology, Vol. 191, No. 2, 2013, p. 561-571.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - HLA peptide length preferences control CD8+ T cell responses

AU - Rist, Melissa J

AU - Theodossis, Alexander

AU - Croft, Nathan Paul

AU - Neller, Michelle A

AU - Welland, Andrew David

AU - Chen, Zhenjun

AU - Sullivan, Lucy C

AU - Burrows, Jacqueline M

AU - Miles, John J

AU - Brennan, Rebekah M

AU - Gras, Stephanie

AU - Khanna, Rajiv

AU - Brooks, Andrew

AU - McCluskey, James

AU - Purcell, Anthony Wayne

AU - Rossjohn, Jamie

AU - Burrows, Scott R

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.jimmunol.org/content/191/2/561.full.pdf

U2 - 10.4049/jimmunol.1300292

DO - 10.4049/jimmunol.1300292

M3 - Article

VL - 191

SP - 561

EP - 571

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -