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A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees
Examining CD8(+) and CD4(+) T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8(+) and 50 CD4(+) T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HL...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489334/ https://www.ncbi.nlm.nih.gov/pubmed/32983097 http://dx.doi.org/10.3389/fimmu.2020.01836 |
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author | Stryhn, Anette Kongsgaard, Michael Rasmussen, Michael Harndahl, Mikkel Nors Østerbye, Thomas Bassi, Maria Rosaria Thybo, Søren Gabriel, Mette Hansen, Morten Bagge Nielsen, Morten Christensen, Jan Pravsgaard Randrup Thomsen, Allan Buus, Soren |
author_facet | Stryhn, Anette Kongsgaard, Michael Rasmussen, Michael Harndahl, Mikkel Nors Østerbye, Thomas Bassi, Maria Rosaria Thybo, Søren Gabriel, Mette Hansen, Morten Bagge Nielsen, Morten Christensen, Jan Pravsgaard Randrup Thomsen, Allan Buus, Soren |
author_sort | Stryhn, Anette |
collection | PubMed |
description | Examining CD8(+) and CD4(+) T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8(+) and 50 CD4(+) T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4(+) T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4(+) T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4(+) T cell responses. Our T cell epitope discovery approach uses a combination of (1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4(+) and/or CD8(+) T cell epitopes, (2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, (3) generation of peptide-HLA tetramers to identify T cell epitopes, and (4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4(+) and CD8(+) T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g., SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses. |
format | Online Article Text |
id | pubmed-7489334 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74893342020-09-25 A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees Stryhn, Anette Kongsgaard, Michael Rasmussen, Michael Harndahl, Mikkel Nors Østerbye, Thomas Bassi, Maria Rosaria Thybo, Søren Gabriel, Mette Hansen, Morten Bagge Nielsen, Morten Christensen, Jan Pravsgaard Randrup Thomsen, Allan Buus, Soren Front Immunol Immunology Examining CD8(+) and CD4(+) T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8(+) and 50 CD4(+) T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4(+) T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4(+) T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4(+) T cell responses. Our T cell epitope discovery approach uses a combination of (1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4(+) and/or CD8(+) T cell epitopes, (2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, (3) generation of peptide-HLA tetramers to identify T cell epitopes, and (4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4(+) and CD8(+) T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g., SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses. Frontiers Media S.A. 2020-08-31 /pmc/articles/PMC7489334/ /pubmed/32983097 http://dx.doi.org/10.3389/fimmu.2020.01836 Text en Copyright © 2020 Stryhn, Kongsgaard, Rasmussen, Harndahl, Østerbye, Bassi, Thybo, Gabriel, Hansen, Nielsen, Christensen, Randrup Thomsen and Buus. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Stryhn, Anette Kongsgaard, Michael Rasmussen, Michael Harndahl, Mikkel Nors Østerbye, Thomas Bassi, Maria Rosaria Thybo, Søren Gabriel, Mette Hansen, Morten Bagge Nielsen, Morten Christensen, Jan Pravsgaard Randrup Thomsen, Allan Buus, Soren A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title | A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title_full | A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title_fullStr | A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title_full_unstemmed | A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title_short | A Systematic, Unbiased Mapping of CD8(+) and CD4(+) T Cell Epitopes in Yellow Fever Vaccinees |
title_sort | systematic, unbiased mapping of cd8(+) and cd4(+) t cell epitopes in yellow fever vaccinees |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489334/ https://www.ncbi.nlm.nih.gov/pubmed/32983097 http://dx.doi.org/10.3389/fimmu.2020.01836 |
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