Differential Recognition of Influenza A Viruses by M158–66 Epitope-Specific CD8+ T Cells Is Determined by Extraepitopic Amino Acid Residues
Identifieur interne : 000576 ( Main/Merge ); précédent : 000575; suivant : 000577Differential Recognition of Influenza A Viruses by M158–66 Epitope-Specific CD8+ T Cells Is Determined by Extraepitopic Amino Acid Residues
Auteurs : Carolien E. Van De Sandt [Pays-Bas] ; Joost H. C. M. Kreijtz [Pays-Bas] ; Martina M. Geelhoed-Mieras [Pays-Bas] ; Nella J. Nieuwkoop [Pays-Bas] ; Monique I. Spronken [Pays-Bas] ; David A. M. C. Van De Vijver [Pays-Bas] ; Ron A. M. Fouchier [Pays-Bas] ; Albert D. M. E. Osterhaus [Pays-Bas] ; Guus F. Rimmelzwaan [Pays-Bas]Source :
- Journal of Virology [ 0022-538X ] ; 2015.
Abstract
Natural influenza A virus infections elicit both virus-specific antibody and CD4+ and CD8+ T cell responses. Influenza A virus-specific CD8+ cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M158–66) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M158–66 epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8+ T cell recognition of the M158–66 epitope. These data indicate that human influenza A viruses can impair recognition by M158–66-specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses.
Url:
DOI: 10.1128/JVI.02439-15
PubMed: 26537686
PubMed Central: 4702701
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Epitope-Specific CD8<sup>+</sup>
T Cells Is Determined by Extraepitopic Amino Acid Residues</title>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Differential Recognition of Influenza A Viruses by M1<sub>58–66</sub>
Epitope-Specific CD8<sup>+</sup>
T Cells Is Determined by Extraepitopic Amino Acid Residues</title>
<author><name sortKey="Van De Sandt, Carolien E" sort="Van De Sandt, Carolien E" uniqKey="Van De Sandt C" first="Carolien E." last="Van De Sandt">Carolien E. Van De Sandt</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
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<author><name sortKey="Kreijtz, Joost H C M" sort="Kreijtz, Joost H C M" uniqKey="Kreijtz J" first="Joost H. C. M." last="Kreijtz">Joost H. C. M. Kreijtz</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Viroscience, Erasmus MC, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
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<author><name sortKey="Geelhoed Mieras, Martina M" sort="Geelhoed Mieras, Martina M" uniqKey="Geelhoed Mieras M" first="Martina M." last="Geelhoed-Mieras">Martina M. Geelhoed-Mieras</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
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<author><name sortKey="Nieuwkoop, Nella J" sort="Nieuwkoop, Nella J" uniqKey="Nieuwkoop N" first="Nella J." last="Nieuwkoop">Nella J. Nieuwkoop</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
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<author><name sortKey="Spronken, Monique I" sort="Spronken, Monique I" uniqKey="Spronken M" first="Monique I." last="Spronken">Monique I. Spronken</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
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<placeName><settlement type="city">Rotterdam</settlement>
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</placeName>
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<author><name sortKey="Van De Vijver, David A M C" sort="Van De Vijver, David A M C" uniqKey="Van De Vijver D" first="David A. M. C." last="Van De Vijver">David A. M. C. Van De Vijver</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Viroscience, Erasmus MC, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fouchier, Ron A M" sort="Fouchier, Ron A M" uniqKey="Fouchier R" first="Ron A. M." last="Fouchier">Ron A. M. Fouchier</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Viroscience, Erasmus MC, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
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<author><name sortKey="Osterhaus, Albert D M E" sort="Osterhaus, Albert D M E" uniqKey="Osterhaus A" first="Albert D. M. E." last="Osterhaus">Albert D. M. E. Osterhaus</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Viroscience, Erasmus MC, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
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<affiliation wicri:level="3"><nlm:aff id="aff2">ViroClinics Biosciences BV, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>ViroClinics Biosciences BV, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
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</author>
<author><name sortKey="Rimmelzwaan, Guus F" sort="Rimmelzwaan, Guus F" uniqKey="Rimmelzwaan G" first="Guus F." last="Rimmelzwaan">Guus F. Rimmelzwaan</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Viroscience, Erasmus MC, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">ViroClinics Biosciences BV, Rotterdam, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>ViroClinics Biosciences BV, Rotterdam</wicri:regionArea>
<placeName><settlement type="city">Rotterdam</settlement>
<region nuts="2" type="province">Hollande-Méridionale</region>
</placeName>
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<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2015">2015</date>
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<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Natural influenza A virus infections elicit both virus-specific antibody and CD4<sup>+</sup>
and CD8<sup>+</sup>
T cell responses. Influenza A virus-specific CD8<sup>+</sup>
cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201-restricted matrix protein 1 (M1<sub>58–66</sub>
) epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extraepitopic amino acid substitutions. Activation of specific T cells was used as an indication of antigen presentation. Here, we show that the M1<sub>58–66</sub>
epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrate that naturally occurring variations at extraepitopic amino acid residues affect CD8<sup>+</sup>
T cell recognition of the M1<sub>58–66</sub>
epitope. These data indicate that human influenza A viruses can impair recognition by M1<sub>58–66</sub>
-specific CTLs while retaining the conserved amino acid sequence of the epitope, which may represent a yet-unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses.
</p>
<p><bold>IMPORTANCE</bold>
Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8<sup>+</sup>
cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes, mutations occur that allow influenza A viruses to evade recognition by CTLs. However, the immunodominant HLA-A*0201-restricted M1<sub>58–66</sub>
epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M1<sub>58–66</sub>
epitope that influence the recognition of the epitope. These results provide novel insights into the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.</p>
</div>
</front>
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