Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses

Sophie A Valkenburg, Tracy M Josephs, E Bridie Clemens, Emma J Grant, Thi H O Nguyen, George C Wang, David A Price, Adrian Miller, Steven Y C Tong, Paul G Thomas, Peter C Doherty, Jamie Rossjohn, Stephanie Gras, Katherine Kedzierska

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31 Citations (Scopus)

Abstract

Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A∗0201-M158 and the hypervariable HLA-B∗3501-NP418 antigens. The TCRαβs for HLA-B∗3501-NP418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A∗0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A∗0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A∗0201+ individuals. Combined with the high population frequency of HLA-A∗0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.
Original languageEnglish
Pages (from-to)4440-4445
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume113
Issue number16
DOIs
Publication statusPublished - 19 Apr 2016

Keywords

  • influenza infection
  • human CD8+ T cells
  • T-cell receptor

Cite this

Valkenburg, Sophie A ; Josephs, Tracy M ; Clemens, E Bridie ; Grant, Emma J ; Nguyen, Thi H O ; Wang, George C ; Price, David A ; Miller, Adrian ; Tong, Steven Y C ; Thomas, Paul G ; Doherty, Peter C ; Rossjohn, Jamie ; Gras, Stephanie ; Kedzierska, Katherine. / Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses. In: Proceedings of the National Academy of Sciences. 2016 ; Vol. 113, No. 16. pp. 4440-4445.
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abstract = "Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A∗0201-M158 and the hypervariable HLA-B∗3501-NP418 antigens. The TCRαβs for HLA-B∗3501-NP418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A∗0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A∗0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A∗0201+ individuals. Combined with the high population frequency of HLA-A∗0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.",
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author = "Valkenburg, {Sophie A} and Josephs, {Tracy M} and Clemens, {E Bridie} and Grant, {Emma J} and Nguyen, {Thi H O} and Wang, {George C} and Price, {David A} and Adrian Miller and Tong, {Steven Y C} and Thomas, {Paul G} and Doherty, {Peter C} and Jamie Rossjohn and Stephanie Gras and Katherine Kedzierska",
year = "2016",
month = "4",
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Valkenburg, SA, Josephs, TM, Clemens, EB, Grant, EJ, Nguyen, THO, Wang, GC, Price, DA, Miller, A, Tong, SYC, Thomas, PG, Doherty, PC, Rossjohn, J, Gras, S & Kedzierska, K 2016, 'Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses', Proceedings of the National Academy of Sciences, vol. 113, no. 16, pp. 4440-4445. https://doi.org/10.1073/pnas.1603106113

Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses. / Valkenburg, Sophie A; Josephs, Tracy M; Clemens, E Bridie; Grant, Emma J; Nguyen, Thi H O; Wang, George C; Price, David A; Miller, Adrian; Tong, Steven Y C; Thomas, Paul G; Doherty, Peter C; Rossjohn, Jamie; Gras, Stephanie; Kedzierska, Katherine.

In: Proceedings of the National Academy of Sciences, Vol. 113, No. 16, 19.04.2016, p. 4440-4445.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses

AU - Valkenburg, Sophie A

AU - Josephs, Tracy M

AU - Clemens, E Bridie

AU - Grant, Emma J

AU - Nguyen, Thi H O

AU - Wang, George C

AU - Price, David A

AU - Miller, Adrian

AU - Tong, Steven Y C

AU - Thomas, Paul G

AU - Doherty, Peter C

AU - Rossjohn, Jamie

AU - Gras, Stephanie

AU - Kedzierska, Katherine

PY - 2016/4/19

Y1 - 2016/4/19

N2 - Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A∗0201-M158 and the hypervariable HLA-B∗3501-NP418 antigens. The TCRαβs for HLA-B∗3501-NP418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A∗0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A∗0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A∗0201+ individuals. Combined with the high population frequency of HLA-A∗0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.

AB - Memory CD8+ T lymphocytes (CTLs) specific for antigenic peptides derived from internal viral proteins confer broad protection against distinct strains of influenza A virus (IAV). However, immune efficacy can be undermined by the emergence of escape mutants. To determine how T-cell receptor (TCR) composition relates to IAV epitope variability, we used ex vivo peptide-HLA tetramer enrichment and single-cell multiplex analysis to compare TCRs targeted to the largely conserved HLA-A∗0201-M158 and the hypervariable HLA-B∗3501-NP418 antigens. The TCRαβs for HLA-B∗3501-NP418 + CTLs varied among individuals and across IAV strains, indicating that a range of mutated peptides will prime different NP418-specific CTL sets. Conversely, a dominant public TRAV27/TRBV19+ TCRαβ was selected in HLA-A∗0201+ donors responding to M158. This public TCR cross-recognized naturally occurring M158 variants complexed with HLA-A∗0201. Ternary structures showed that induced-fit molecular mimicry underpins TRAV27/TRBV19+ TCR specificity for the WT and mutant M158 peptides, suggesting the possibility of universal CTL immunity in HLA-A∗0201+ individuals. Combined with the high population frequency of HLA-A∗0201, these data potentially explain the relative conservation of M158. Moreover, our results suggest that vaccination strategies aimed at generating broad protection should incorporate variant peptides to elicit cross-reactive responses against other specificities, especially those that may be relatively infrequent among IAV-primed memory CTLs.

KW - influenza infection

KW - human CD8+ T cells

KW - T-cell receptor

UR - http://www.ncbi.nlm.nih.gov/pubmed/27036003

U2 - 10.1073/pnas.1603106113

DO - 10.1073/pnas.1603106113

M3 - Article

VL - 113

SP - 4440

EP - 4445

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 16

ER -