Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins!
Identifieur interne : 003060 ( Main/Merge ); précédent : 003059; suivant : 003061Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins!
Auteurs : J. T. Gerlach [Suisse, Allemagne] ; A. Ulsenheimer [Allemagne] ; N. H. Grüner [Allemagne] ; M.-C. June [Allemagne] ; W. Schraut [Allemagne] ; C.-A. Schirren [Allemagne] ; M. Heeg [Allemagne] ; S. Scholz [Allemagne] ; K. Witter [Allemagne] ; R. Zahn [Allemagne] ; A. Vogler [Allemagne] ; R. Zachoval [Allemagne] ; G. R. Pape [Allemagne] ; H. M. Diepolder [Allemagne]Source :
- Journal of virology [ 0022-538X ] ; 2005.
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Abstract
The hepatitis C virus (HCV)-specific CD4+ T-cell response against nonstructural proteins is strongly associated with successful viral clearance during acute hepatitis C. To further develop these observations into peptide-based vaccines and clinical immunomonitoring tools like HLA class II tetramers, a detailed characterization of immunodominant CD4+ T-cell epitopes is required. We studied peripheral blood mononuclear cells from 20 patients with acute hepatitis C using 83 overlapping 20-mer peptides covering the NS3 helicase and NS4. Eight peptides were recognized by ≥40% of patients, and specific CD4+ T-cell clones were obtained for seven of these and three additional, subdominant epitopes. Mapping of minimal stimulatory sequences defined epitopes of 8 to 13 amino acids in length, but optimal T-cell stimulation was observed with 10- to 15-mers. While some epitopes were presented by different HLA molecules, others were presented by only a single HLA class II molecule, which has implications for patient selection in clinical trials of peptide-based immunotherapies. In conclusion, using two different approaches we identified and characterized a set of CD4+ T-cell epitopes in the HCV NS3-NS4 region which are immunodominant in patients achieving transient or persistent viral control. This information allows the construction of a valuable panel of HCV-specific HLA class II tetramers for further study of CD4+ T-cell responses in chronic hepatitis C. The finding of immunodominant epitopes with very constrained HLA restriction has implications for patient selection in clinical trials of peptide-based immunotherapies.
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Pascal:05-0432453Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4<sup>+</sup>
T-cell epitopes within hepatitis C virus NS3 and NS4 proteins!</title>
<author><name sortKey="Gerlach, J T" sort="Gerlach, J T" uniqKey="Gerlach J" first="J. T." last="Gerlach">J. T. Gerlach</name>
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<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Gruner, N H" sort="Gruner, N H" uniqKey="Gruner N" first="N. H." last="Grüner">N. H. Grüner</name>
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<settlement type="city">Munich</settlement>
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<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
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<settlement type="city">Munich</settlement>
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<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
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</author>
<author><name sortKey="June, M C" sort="June, M C" uniqKey="June M" first="M.-C." last="June">M.-C. June</name>
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<s2>80336 Munich</s2>
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<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Schraut, W" sort="Schraut, W" uniqKey="Schraut W" first="W." last="Schraut">W. Schraut</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Institute for Immunology, University of Munich</s1>
<s2>80336 Munich</s2>
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<country>Allemagne</country>
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<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Schirren, C A" sort="Schirren, C A" uniqKey="Schirren C" first="C.-A." last="Schirren">C.-A. Schirren</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
<s3>DEU</s3>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Heeg, M" sort="Heeg, M" uniqKey="Heeg M" first="M." last="Heeg">M. Heeg</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Institute for Immunology, University of Munich</s1>
<s2>80336 Munich</s2>
<s3>DEU</s3>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Scholz, S" sort="Scholz, S" uniqKey="Scholz S" first="S." last="Scholz">S. Scholz</name>
<affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Immunogenetics Laboratory, Kinderpoliklinik, University of Munich</s1>
<s2>80336 Munich</s2>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Witter, K" sort="Witter, K" uniqKey="Witter K" first="K." last="Witter">K. Witter</name>
<affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Immunogenetics Laboratory, Kinderpoliklinik, University of Munich</s1>
<s2>80336 Munich</s2>
<s3>DEU</s3>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Zahn, R" sort="Zahn, R" uniqKey="Zahn R" first="R." last="Zahn">R. Zahn</name>
<affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Immunogenetics Laboratory, Kinderpoliklinik, University of Munich</s1>
<s2>80336 Munich</s2>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
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</author>
<author><name sortKey="Vogler, A" sort="Vogler, A" uniqKey="Vogler A" first="A." last="Vogler">A. Vogler</name>
<affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Immunogenetics Laboratory, Kinderpoliklinik, University of Munich</s1>
<s2>80336 Munich</s2>
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<sZ>8 aut.</sZ>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
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</author>
<author><name sortKey="Zachoval, R" sort="Zachoval, R" uniqKey="Zachoval R" first="R." last="Zachoval">R. Zachoval</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
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<country>Allemagne</country>
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<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
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</author>
<author><name sortKey="Pape, G R" sort="Pape, G R" uniqKey="Pape G" first="G. R." last="Pape">G. R. Pape</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Institute for Immunology, University of Munich</s1>
<s2>80336 Munich</s2>
<s3>DEU</s3>
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<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
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<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
<author><name sortKey="Diepolder, H M" sort="Diepolder, H M" uniqKey="Diepolder H" first="H. M." last="Diepolder">H. M. Diepolder</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Institute for Immunology, University of Munich</s1>
<s2>80336 Munich</s2>
<s3>DEU</s3>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Medicine II, Klinikum Grosshadem, University of Munich</s1>
<s2>81377 Munich</s2>
<s3>DEU</s3>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
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<country>Allemagne</country>
<placeName><region type="land" nuts="1">Bavière</region>
<region type="district" nuts="2">District de Haute-Bavière</region>
<settlement type="city">Munich</settlement>
</placeName>
<orgName type="university">Université Louis-et-Maximilien de Munich</orgName>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Journal of virology</title>
<title level="j" type="abbreviated">J. virol.</title>
<idno type="ISSN">0022-538X</idno>
<imprint><date when="2005">2005</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Journal of virology</title>
<title level="j" type="abbreviated">J. virol.</title>
<idno type="ISSN">0022-538X</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigenic determinant</term>
<term>HLA-System</term>
<term>Hepatitis C virus</term>
<term>Immunodominance</term>
<term>Microbiology</term>
<term>Protein</term>
<term>T-Lymphocyte</term>
<term>Virology</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Virus hépatite C</term>
<term>Lymphocyte T</term>
<term>Système HLA</term>
<term>Immunodominance</term>
<term>Déterminant antigénique</term>
<term>Protéine</term>
<term>Microbiologie</term>
<term>Virologie</term>
<term>Antigène CD4</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The hepatitis C virus (HCV)-specific CD4<sup>+</sup>
T-cell response against nonstructural proteins is strongly associated with successful viral clearance during acute hepatitis C. To further develop these observations into peptide-based vaccines and clinical immunomonitoring tools like HLA class II tetramers, a detailed characterization of immunodominant CD4<sup>+</sup>
T-cell epitopes is required. We studied peripheral blood mononuclear cells from 20 patients with acute hepatitis C using 83 overlapping 20-mer peptides covering the NS3 helicase and NS4. Eight peptides were recognized by ≥40% of patients, and specific CD4<sup>+</sup>
T-cell clones were obtained for seven of these and three additional, subdominant epitopes. Mapping of minimal stimulatory sequences defined epitopes of 8 to 13 amino acids in length, but optimal T-cell stimulation was observed with 10- to 15-mers. While some epitopes were presented by different HLA molecules, others were presented by only a single HLA class II molecule, which has implications for patient selection in clinical trials of peptide-based immunotherapies. In conclusion, using two different approaches we identified and characterized a set of CD4<sup>+</sup>
T-cell epitopes in the HCV NS3-NS4 region which are immunodominant in patients achieving transient or persistent viral control. This information allows the construction of a valuable panel of HCV-specific HLA class II tetramers for further study of CD4<sup>+</sup>
T-cell responses in chronic hepatitis C. The finding of immunodominant epitopes with very constrained HLA restriction has implications for patient selection in clinical trials of peptide-based immunotherapies.</div>
</front>
</TEI>
<affiliations><list><country><li>Allemagne</li>
<li>Suisse</li>
</country>
<region><li>Bavière</li>
<li>District de Haute-Bavière</li>
</region>
<settlement><li>Munich</li>
</settlement>
<orgName><li>Université Louis-et-Maximilien de Munich</li>
</orgName>
</list>
<tree><country name="Suisse"><noRegion><name sortKey="Gerlach, J T" sort="Gerlach, J T" uniqKey="Gerlach J" first="J. T." last="Gerlach">J. T. Gerlach</name>
</noRegion>
</country>
<country name="Allemagne"><region name="Bavière"><name sortKey="Gerlach, J T" sort="Gerlach, J T" uniqKey="Gerlach J" first="J. T." last="Gerlach">J. T. Gerlach</name>
</region>
<name sortKey="Diepolder, H M" sort="Diepolder, H M" uniqKey="Diepolder H" first="H. M." last="Diepolder">H. M. Diepolder</name>
<name sortKey="Diepolder, H M" sort="Diepolder, H M" uniqKey="Diepolder H" first="H. M." last="Diepolder">H. M. Diepolder</name>
<name sortKey="Gruner, N H" sort="Gruner, N H" uniqKey="Gruner N" first="N. H." last="Grüner">N. H. Grüner</name>
<name sortKey="Gruner, N H" sort="Gruner, N H" uniqKey="Gruner N" first="N. H." last="Grüner">N. H. Grüner</name>
<name sortKey="Heeg, M" sort="Heeg, M" uniqKey="Heeg M" first="M." last="Heeg">M. Heeg</name>
<name sortKey="June, M C" sort="June, M C" uniqKey="June M" first="M.-C." last="June">M.-C. June</name>
<name sortKey="June, M C" sort="June, M C" uniqKey="June M" first="M.-C." last="June">M.-C. June</name>
<name sortKey="Pape, G R" sort="Pape, G R" uniqKey="Pape G" first="G. R." last="Pape">G. R. Pape</name>
<name sortKey="Pape, G R" sort="Pape, G R" uniqKey="Pape G" first="G. R." last="Pape">G. R. Pape</name>
<name sortKey="Schirren, C A" sort="Schirren, C A" uniqKey="Schirren C" first="C.-A." last="Schirren">C.-A. Schirren</name>
<name sortKey="Scholz, S" sort="Scholz, S" uniqKey="Scholz S" first="S." last="Scholz">S. Scholz</name>
<name sortKey="Schraut, W" sort="Schraut, W" uniqKey="Schraut W" first="W." last="Schraut">W. Schraut</name>
<name sortKey="Ulsenheimer, A" sort="Ulsenheimer, A" uniqKey="Ulsenheimer A" first="A." last="Ulsenheimer">A. Ulsenheimer</name>
<name sortKey="Ulsenheimer, A" sort="Ulsenheimer, A" uniqKey="Ulsenheimer A" first="A." last="Ulsenheimer">A. Ulsenheimer</name>
<name sortKey="Vogler, A" sort="Vogler, A" uniqKey="Vogler A" first="A." last="Vogler">A. Vogler</name>
<name sortKey="Witter, K" sort="Witter, K" uniqKey="Witter K" first="K." last="Witter">K. Witter</name>
<name sortKey="Zachoval, R" sort="Zachoval, R" uniqKey="Zachoval R" first="R." last="Zachoval">R. Zachoval</name>
<name sortKey="Zahn, R" sort="Zahn, R" uniqKey="Zahn R" first="R." last="Zahn">R. Zahn</name>
</country>
</tree>
</affiliations>
</record>
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