A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires
Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, t...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:f93445a02b2b471c835e0f59d15270592021-12-01T20:02:45ZA Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires1664-322410.3389/fimmu.2021.735584https://doaj.org/article/f93445a02b2b471c835e0f59d15270592021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.735584/fullhttps://doaj.org/toc/1664-3224Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous ‘Clusters of Expanded TCRs (CETs)’ can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.Valentina CegliaValentina CegliaValentina CegliaErin J. KelleyAnnalee S. BoyleSandra ZurawskiSandra ZurawskiHeather L. MeadCaroline E. HarmsJean-Philippe BlanckAnne-Laure FlamarAnne-Laure FlamarAnne-Laure FlamarJung Hwa KirschmanPaul OgongoJoel D. ErnstYves LevyYves LevyGerard ZurawskiGerard ZurawskiJohn A. AltinFrontiers Media S.A.articleT cell receptor (TCR)T cell responsesvaccinesdendritic cellsmonoclonal antibodiesTCR sequencingImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
T cell receptor (TCR) T cell responses vaccines dendritic cells monoclonal antibodies TCR sequencing Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
T cell receptor (TCR) T cell responses vaccines dendritic cells monoclonal antibodies TCR sequencing Immunologic diseases. Allergy RC581-607 Valentina Ceglia Valentina Ceglia Valentina Ceglia Erin J. Kelley Annalee S. Boyle Sandra Zurawski Sandra Zurawski Heather L. Mead Caroline E. Harms Jean-Philippe Blanck Anne-Laure Flamar Anne-Laure Flamar Anne-Laure Flamar Jung Hwa Kirschman Paul Ogongo Joel D. Ernst Yves Levy Yves Levy Gerard Zurawski Gerard Zurawski John A. Altin A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| description |
Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous ‘Clusters of Expanded TCRs (CETs)’ can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity. |
| format |
article |
| author |
Valentina Ceglia Valentina Ceglia Valentina Ceglia Erin J. Kelley Annalee S. Boyle Sandra Zurawski Sandra Zurawski Heather L. Mead Caroline E. Harms Jean-Philippe Blanck Anne-Laure Flamar Anne-Laure Flamar Anne-Laure Flamar Jung Hwa Kirschman Paul Ogongo Joel D. Ernst Yves Levy Yves Levy Gerard Zurawski Gerard Zurawski John A. Altin |
| author_facet |
Valentina Ceglia Valentina Ceglia Valentina Ceglia Erin J. Kelley Annalee S. Boyle Sandra Zurawski Sandra Zurawski Heather L. Mead Caroline E. Harms Jean-Philippe Blanck Anne-Laure Flamar Anne-Laure Flamar Anne-Laure Flamar Jung Hwa Kirschman Paul Ogongo Joel D. Ernst Yves Levy Yves Levy Gerard Zurawski Gerard Zurawski John A. Altin |
| author_sort |
Valentina Ceglia |
| title |
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| title_short |
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| title_full |
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| title_fullStr |
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| title_full_unstemmed |
A Framework to Identify Antigen-Expanded T Cell Receptor Clusters Within Complex Repertoires |
| title_sort |
framework to identify antigen-expanded t cell receptor clusters within complex repertoires |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/f93445a02b2b471c835e0f59d1527059 |
| work_keys_str_mv |
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