Building and Optimizing a Virus-specific T Cell Receptor Library for Targeted Immunotherapy in Viral Infections
Identifieur interne : 000427 ( Ncbi/Merge ); précédent : 000426; suivant : 000428Building and Optimizing a Virus-specific T Cell Receptor Library for Targeted Immunotherapy in Viral Infections
Auteurs : Nasirah Banu ; Adeline Chia ; Zi Zong Ho ; Alfonso Tan Garcia ; Komathi Paravasivam ; Gijsbert M. Grotenbreg ; Antonio Bertoletti ; Adam J. GehringSource :
- Scientific Reports [ 2045-2322 ] ; 2014.
Abstract
Restoration of antigen-specific T cell immunity has the potential to clear persistent viral infection. T cell receptor (TCR) gene therapy can reconstitute CD8 T cell immunity in chronic patients. We cloned 10 virus-specific TCRs targeting 5 different viruses, causing chronic and acute infection. All 10 TCR genetic constructs were optimized for expression using a P2A sequence, codon optimization and the addition of a non-native disulfide bond. However, maximum TCR expression was only achieved after establishing the optimal orientation of the alpha and beta chains in the expression cassette; 9/10 TCRs favored the beta-P2A-alpha orientation over alpha-P2A-beta. Optimal TCR expression was associated with a significant increase in the frequency of IFN-gamma+ T cells. In addition, activating cells for transduction in the presence of Toll-like receptor ligands further enhanced IFN-gamma production. Thus, we have built a virus-specific TCR library that has potential for therapeutic intervention in chronic viral infection or virus-related cancers.
Url:
DOI: 10.1038/srep04166
PubMed: 24566718
PubMed Central: 3933865
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- to stream Pmc, to step Curation: 000325
- to stream Pmc, to step Checkpoint: 000650
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PMC:3933865Le document en format XML
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Gehring</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.452264.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 0530 269X</institution-id><institution>Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star),</institution></institution-wrap>Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.262962.b</institution-id><institution-id institution-id-type="ISNI">0000 0004 1936 9342</institution-id><institution>Molecular Microbiology and Immunology, Saint Louis University School of Medicine,</institution></institution-wrap>Saint Louis, Missouri USA</nlm:aff><wicri:noCountry code="subfield">Missouri USA</wicri:noCountry></affiliation><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.262962.b</institution-id><institution-id institution-id-type="ISNI">0000 0004 1936 9342</institution-id><institution>Saint Louis University Liver Center, Saint Louis University School of Medicine,</institution></institution-wrap>Saint Louis, Missouri USA</nlm:aff><wicri:noCountry code="subfield">Missouri USA</wicri:noCountry></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Restoration of antigen-specific T cell immunity has the potential to clear persistent viral infection. T cell receptor (TCR) gene therapy can reconstitute CD8 T cell immunity in chronic patients. We cloned 10 virus-specific TCRs targeting 5 different viruses, causing chronic and acute infection. All 10 TCR genetic constructs were optimized for expression using a P2A sequence, codon optimization and the addition of a non-native disulfide bond. However, maximum TCR expression was only achieved after establishing the optimal orientation of the alpha and beta chains in the expression cassette; 9/10 TCRs favored the beta-P2A-alpha orientation over alpha-P2A-beta. Optimal TCR expression was associated with a significant increase in the frequency of IFN-gamma+ T cells. In addition, activating cells for transduction in the presence of Toll-like receptor ligands further enhanced IFN-gamma production. Thus, we have built a virus-specific TCR library that has potential for therapeutic intervention in chronic viral infection or virus-related cancers.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bertoletti, A" uniqKey="Bertoletti A">A Bertoletti</name></author><author><name sortKey="Ferrari, C" uniqKey="Ferrari C">C Ferrari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pagliara, D" uniqKey="Pagliara D">D Pagliara</name></author><author><name sortKey="Savoldo, B" uniqKey="Savoldo B">B Savoldo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Gk" uniqKey="Lau G">GK Lau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Gkk" uniqKey="Lau G">GKK Lau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loggi, E" uniqKey="Loggi E">E Loggi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cobbold, M" uniqKey="Cobbold M">M Cobbold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rooney, Cm" uniqKey="Rooney C">CM Rooney</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sridhar, S" uniqKey="Sridhar S">S Sridhar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oh, Hlj" uniqKey="Oh H">HLJ Oh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gehring, Aj" uniqKey="Gehring A">AJ Gehring</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sung, W K" uniqKey="Sung W">W-K Sung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Szymczak, Al" uniqKey="Szymczak A">AL Szymczak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, S" uniqKey="Yang S">S Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuball, J" uniqKey="Kuball J">J Kuball</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cohen, Cj" uniqKey="Cohen C">CJ Cohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scholten, Kbj" uniqKey="Scholten K">KBJ Scholten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Engels, B" uniqKey="Engels B">B Engels</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leisegang, M" uniqKey="Leisegang M">M Leisegang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caron, G" uniqKey="Caron G">G Caron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhu, Q" uniqKey="Zhu Q">Q Zhu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haga Friedman, A" uniqKey="Haga Friedman A">A Haga-Friedman</name></author><author><name sortKey="Horovitz Fried, M" uniqKey="Horovitz Fried M">M Horovitz-Fried</name></author><author><name sortKey="Cohen, Cj" uniqKey="Cohen C">CJ Cohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okamoto, S" uniqKey="Okamoto S">S Okamoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aggen, Dh" uniqKey="Aggen D">DH Aggen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sommermeyer, D" uniqKey="Sommermeyer D">D Sommermeyer</name></author><author><name sortKey="Uckert, W" uniqKey="Uckert W">W Uckert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bialer, G" uniqKey="Bialer G">G Bialer</name></author><author><name sortKey="Horovitz Fried, M" uniqKey="Horovitz Fried M">M Horovitz-Fried</name></author><author><name sortKey="Ya Acobi, S" uniqKey="Ya Acobi S">S Ya'acobi</name></author><author><name sortKey="Morgan, Ra" uniqKey="Morgan R">RA Morgan</name></author><author><name sortKey="Cohen, Cj" uniqKey="Cohen C">CJ Cohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Voss, R H" uniqKey="Voss R">R-H Voss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sebestyen, Z" uniqKey="Sebestyen Z">Z Sebestyén</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cohen, Cj" uniqKey="Cohen C">CJ Cohen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, S" uniqKey="Yang S">S Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hinrichs, Cs" uniqKey="Hinrichs C">CS Hinrichs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koh, S" uniqKey="Koh S">S Koh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kearse, Kp" 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Chang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24566718</article-id><article-id pub-id-type="pmc">3933865</article-id><article-id pub-id-type="publisher-id">BFsrep04166</article-id><article-id pub-id-type="doi">10.1038/srep04166</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Building and Optimizing a Virus-specific T Cell Receptor Library for Targeted Immunotherapy in Viral Infections</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Banu</surname><given-names>Nasirah</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chia</surname><given-names>Adeline</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ho</surname><given-names>Zi Zong</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Garcia</surname><given-names>Alfonso Tan</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Paravasivam</surname><given-names>Komathi</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Grotenbreg</surname><given-names>Gijsbert M.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Bertoletti</surname><given-names>Antonio</given-names></name><address><email>Antonio@sics.a-star.edu.sg</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Gehring</surname><given-names>Adam J.</given-names></name><address><email>gehringa@slu.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.452264.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 0530 269X</institution-id><institution>Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star),</institution></institution-wrap>Singapore</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.4280.e</institution-id><institution-id institution-id-type="ISNI">0000 0001 2180 6431</institution-id><institution>Departments of Microbiology and Biological Sciences,</institution><institution>Immunology Programme, National University of Singapore,</institution></institution-wrap>Singapore</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.4280.e</institution-id><institution-id institution-id-type="ISNI">0000 0001 2180 6431</institution-id><institution>Program of Emerging Viral Diseases, Duke-NUS Graduate Medical School, National University of Singapore,</institution></institution-wrap>Singapore</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.262962.b</institution-id><institution-id institution-id-type="ISNI">0000 0004 1936 9342</institution-id><institution>Molecular Microbiology and Immunology, Saint Louis University School of Medicine,</institution></institution-wrap>Saint Louis, Missouri USA</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.262962.b</institution-id><institution-id institution-id-type="ISNI">0000 0004 1936 9342</institution-id><institution>Saint Louis University Liver Center, Saint Louis University School of Medicine,</institution></institution-wrap>Saint Louis, Missouri USA</aff></contrib-group><pub-date pub-type="epub"><day>25</day><month>2</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>25</day><month>2</month><year>2014</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>4</volume><elocation-id>4166</elocation-id><history><date date-type="received"><day>5</day><month>9</month><year>2013</year></date><date date-type="accepted"><day>3</day><month>2</month><year>2014</year></date></history><permissions><copyright-statement>© The Author(s) 2014</copyright-statement><license license-type="OpenAccess"><license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-sa/3.0/">http://creativecommons.org/licenses/by-nc-sa/3.0/</ext-link></license-p></license></permissions><abstract id="Abs1"><p>Restoration of antigen-specific T cell immunity has the potential to clear persistent viral infection. T cell receptor (TCR) gene therapy can reconstitute CD8 T cell immunity in chronic patients. We cloned 10 virus-specific TCRs targeting 5 different viruses, causing chronic and acute infection. All 10 TCR genetic constructs were optimized for expression using a P2A sequence, codon optimization and the addition of a non-native disulfide bond. However, maximum TCR expression was only achieved after establishing the optimal orientation of the alpha and beta chains in the expression cassette; 9/10 TCRs favored the beta-P2A-alpha orientation over alpha-P2A-beta. Optimal TCR expression was associated with a significant increase in the frequency of IFN-gamma+ T cells. In addition, activating cells for transduction in the presence of Toll-like receptor ligands further enhanced IFN-gamma production. Thus, we have built a virus-specific TCR library that has potential for therapeutic intervention in chronic viral infection or virus-related cancers.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Immunotherapy</kwd><kwd>Viral infection</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2015</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Banu, Nasirah" sort="Banu, Nasirah" uniqKey="Banu N" first="Nasirah" last="Banu">Nasirah Banu</name><name sortKey="Bertoletti, Antonio" sort="Bertoletti, Antonio" uniqKey="Bertoletti A" first="Antonio" last="Bertoletti">Antonio Bertoletti</name><name sortKey="Chia, Adeline" sort="Chia, Adeline" uniqKey="Chia A" first="Adeline" last="Chia">Adeline Chia</name><name sortKey="Garcia, Alfonso Tan" sort="Garcia, Alfonso Tan" uniqKey="Garcia A" first="Alfonso Tan" last="Garcia">Alfonso Tan Garcia</name><name sortKey="Gehring, Adam J" sort="Gehring, Adam J" uniqKey="Gehring A" first="Adam J." last="Gehring">Adam J. Gehring</name><name sortKey="Grotenbreg, Gijsbert M" sort="Grotenbreg, Gijsbert M" uniqKey="Grotenbreg G" first="Gijsbert M." last="Grotenbreg">Gijsbert M. Grotenbreg</name><name sortKey="Ho, Zi Zong" sort="Ho, Zi Zong" uniqKey="Ho Z" first="Zi Zong" last="Ho">Zi Zong Ho</name><name sortKey="Paravasivam, Komathi" sort="Paravasivam, Komathi" uniqKey="Paravasivam K" first="Komathi" last="Paravasivam">Komathi Paravasivam</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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