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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">MHC-derived allopeptide activates TCR-biased CD8<sup>+</sup> Tregs and suppresses organ rejection</title><author><name sortKey="Picarda, Elodie" sort="Picarda, Elodie" uniqKey="Picarda E" first="Elodie" last="Picarda">Elodie Picarda</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Bezie, Severine" sort="Bezie, Severine" uniqKey="Bezie S" first="Séverine" last="Bézie">Séverine Bézie</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Venturi, Vanessa" sort="Venturi, Vanessa" uniqKey="Venturi V" first="Vanessa" last="Venturi">Vanessa Venturi</name><affiliation><nlm:aff id="JCI71533">Computational Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Echasserieau, Klara" sort="Echasserieau, Klara" uniqKey="Echasserieau K" first="Klara" last="Echasserieau">Klara Echasserieau</name><affiliation><nlm:aff id="JCI71533">Plateforme de protéines recombinantes P2R IFR26, Centre de Recherche en Cancérologie Nantes — Angers (CRCNA) UMR892 INSERM, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Merieau, Emmanuel" sort="Merieau, Emmanuel" uniqKey="Merieau E" first="Emmanuel" last="Mérieau">Emmanuel Mérieau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Delhumeau, Aurelie" sort="Delhumeau, Aurelie" uniqKey="Delhumeau A" first="Aurélie" last="Delhumeau">Aurélie Delhumeau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Renaudin, Karine" sort="Renaudin, Karine" uniqKey="Renaudin K" first="Karine" last="Renaudin">Karine Renaudin</name><affiliation><nlm:aff id="JCI71533">Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Brouard, Sophie" sort="Brouard, Sophie" uniqKey="Brouard S" first="Sophie" last="Brouard">Sophie Brouard</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Bernardeau, Karine" sort="Bernardeau, Karine" uniqKey="Bernardeau K" first="Karine" last="Bernardeau">Karine Bernardeau</name><affiliation><nlm:aff id="JCI71533">Plateforme de protéines recombinantes P2R IFR26, Centre de Recherche en Cancérologie Nantes — Angers (CRCNA) UMR892 INSERM, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Anegon, Ignacio" sort="Anegon, Ignacio" uniqKey="Anegon I" first="Ignacio" last="Anegon">Ignacio Anegon</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Guillonneau, Carole" sort="Guillonneau, Carole" uniqKey="Guillonneau C" first="Carole" last="Guillonneau">Carole Guillonneau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24789907</idno><idno type="pmc">4038566</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038566</idno><idno type="RBID">PMC:4038566</idno><idno type="doi">10.1172/JCI71533</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001926</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001926</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">MHC-derived allopeptide activates TCR-biased CD8<sup>+</sup> Tregs and suppresses organ rejection</title><author><name sortKey="Picarda, Elodie" sort="Picarda, Elodie" uniqKey="Picarda E" first="Elodie" last="Picarda">Elodie Picarda</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Bezie, Severine" sort="Bezie, Severine" uniqKey="Bezie S" first="Séverine" last="Bézie">Séverine Bézie</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Venturi, Vanessa" sort="Venturi, Vanessa" uniqKey="Venturi V" first="Vanessa" last="Venturi">Vanessa Venturi</name><affiliation><nlm:aff id="JCI71533">Computational Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia.</nlm:aff></affiliation></author><author><name sortKey="Echasserieau, Klara" sort="Echasserieau, Klara" uniqKey="Echasserieau K" first="Klara" last="Echasserieau">Klara Echasserieau</name><affiliation><nlm:aff id="JCI71533">Plateforme de protéines recombinantes P2R IFR26, Centre de Recherche en Cancérologie Nantes — Angers (CRCNA) UMR892 INSERM, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Merieau, Emmanuel" sort="Merieau, Emmanuel" uniqKey="Merieau E" first="Emmanuel" last="Mérieau">Emmanuel Mérieau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Delhumeau, Aurelie" sort="Delhumeau, Aurelie" uniqKey="Delhumeau A" first="Aurélie" last="Delhumeau">Aurélie Delhumeau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Renaudin, Karine" sort="Renaudin, Karine" uniqKey="Renaudin K" first="Karine" last="Renaudin">Karine Renaudin</name><affiliation><nlm:aff id="JCI71533">Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Brouard, Sophie" sort="Brouard, Sophie" uniqKey="Brouard S" first="Sophie" last="Brouard">Sophie Brouard</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Bernardeau, Karine" sort="Bernardeau, Karine" uniqKey="Bernardeau K" first="Karine" last="Bernardeau">Karine Bernardeau</name><affiliation><nlm:aff id="JCI71533">Plateforme de protéines recombinantes P2R IFR26, Centre de Recherche en Cancérologie Nantes — Angers (CRCNA) UMR892 INSERM, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Anegon, Ignacio" sort="Anegon, Ignacio" uniqKey="Anegon I" first="Ignacio" last="Anegon">Ignacio Anegon</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author><author><name sortKey="Guillonneau, Carole" sort="Guillonneau, Carole" uniqKey="Guillonneau C" first="Carole" last="Guillonneau">Carole Guillonneau</name><affiliation><nlm:aff id="JCI71533">INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</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>In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8<sup>+</sup>CD45RC<sup>lo</sup> regulatory T cells (CD8<sup>+</sup>CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II–derived peptide (Du51) that is recognized by TCR-biased CD8<sup>+</sup>CD40Ig Tregs and activating CD8<sup>+</sup>CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.A<sup>a</sup>/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.A<sup>a</sup>/Du51-specific CD8<sup>+</sup>CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8<sup>+</sup>CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id><journal-id journal-id-type="iso-abbrev">J. Clin. Invest</journal-id><journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id><journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title></journal-title-group><issn pub-type="ppub">0021-9738</issn><issn pub-type="epub">1558-8238</issn><publisher><publisher-name>American Society for Clinical Investigation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24789907</article-id><article-id pub-id-type="pmc">4038566</article-id><article-id pub-id-type="publisher-id">71533</article-id><article-id pub-id-type="doi">10.1172/JCI71533</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>MHC-derived allopeptide activates TCR-biased CD8<sup>+</sup> Tregs and suppresses organ rejection</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Picarda</surname><given-names>Elodie</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Bézie</surname><given-names>Séverine</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Venturi</surname><given-names>Vanessa</given-names></name><xref ref-type="aff" rid="JCI71533">2</xref></contrib><contrib contrib-type="author"><name><surname>Echasserieau</surname><given-names>Klara</given-names></name><xref ref-type="aff" rid="JCI71533">3</xref></contrib><contrib contrib-type="author"><name><surname>Mérieau</surname><given-names>Emmanuel</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Delhumeau</surname><given-names>Aurélie</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Renaudin</surname><given-names>Karine</given-names></name><xref ref-type="aff" rid="JCI71533">4</xref></contrib><contrib contrib-type="author"><name><surname>Brouard</surname><given-names>Sophie</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Bernardeau</surname><given-names>Karine</given-names></name><xref ref-type="aff" rid="JCI71533">3</xref></contrib><contrib contrib-type="author"><name><surname>Anegon</surname><given-names>Ignacio</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib><contrib contrib-type="author"><name><surname>Guillonneau</surname><given-names>Carole</given-names></name><xref ref-type="aff" rid="JCI71533">1</xref></contrib></contrib-group><aff id="JCI71533"><label>1</label>INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUN, Centre Hospitalier Universitaire Nantes, Faculté de Médecine, Université de Nantes, Nantes, France.<label>2</label>Computational Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia.<label>3</label>Plateforme de protéines recombinantes P2R IFR26, Centre de Recherche en Cancérologie Nantes — Angers (CRCNA) UMR892 INSERM, Nantes, France.<label>4</label>Anatomie et Cytologie Pathologiques, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France.</aff><author-notes><corresp>Address correspondence to: Carole Guillonneau, INSERM UMR1064 — Center for Research in Transplantation and Immunology-ITUN, 30 Bd Jean Monnet, 44093, Nantes Cedex 01, France. Phone: 33.2.40087410; Fax: 33.2.40087411; E-mail: <email>carole.guillonneau@univ-nantes.fr</email>.</corresp></author-notes><pub-date pub-type="epub"><day>1</day><month>5</month><year>2014</year></pub-date><pub-date pub-type="ppub"><day>2</day><month>6</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>5</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>124</volume><issue>6</issue><fpage>2497</fpage><lpage>2512</lpage><permissions><copyright-statement>Copyright © 2014, American Society for Clinical Investigation</copyright-statement><copyright-year>2014</copyright-year></permissions><abstract><p>In a rat heart allograft model, preventing T cell costimulation with CD40Ig leads to indefinite allograft survival, which is mediated by the induction of CD8<sup>+</sup>CD45RC<sup>lo</sup> regulatory T cells (CD8<sup>+</sup>CD40Ig Tregs) interacting with plasmacytoid dendritic cells (pDCs). The role of TCR-MHC-peptide interaction in regulating Treg activity remains a topic of debate. Here, we identified a donor MHC class II–derived peptide (Du51) that is recognized by TCR-biased CD8<sup>+</sup>CD40Ig Tregs and activating CD8<sup>+</sup>CD40Ig Tregs in both its phenotype and suppression of antidonor alloreactive T cell responses. We generated a labeled tetramer (MHC-I RT1.A<sup>a</sup>/Du51) to localize and quantify Du51-specific T cells within rat cardiac allografts and spleen. RT1.A<sup>a</sup>/Du51-specific CD8<sup>+</sup>CD40Ig Tregs were the most suppressive subset of the total Treg population, were essential for in vivo tolerance induction, and expressed a biased, restricted Vβ11-TCR repertoire in the spleen and the graft. Finally, we demonstrated that treatment of transplant recipients with the Du51 peptide resulted in indefinite prolongation of allograft survival. These results show that CD8<sup>+</sup>CD40Ig Tregs recognize a dominant donor antigen, resulting in TCR repertoire alterations in the graft and periphery. Furthermore, this allopeptide has strong therapeutic activity and highlights the importance of TCR-peptide-MHC interaction for Treg generation and function.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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