Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses
BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:131 |
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| Enthalten in: |
The Journal of clinical investigation - 131(2021), 10 vom: 17. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dykema, Arbor G [VerfasserIn] |
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| Links: |
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| Themen: |
COVID-19 |
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| Anmerkungen: |
Date Completed 25.05.2021 Date Revised 29.04.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1172/JCI146922 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM32386158X |
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| 100 | 1 | |a Dykema, Arbor G |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 25.05.2021 | ||
| 500 | |a Date Revised 29.04.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a COVID-19 | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a Imprinting | |
| 650 | 4 | |a MHC class 2 | |
| 650 | 4 | |a T cells | |
| 650 | 7 | |a Epitopes, T-Lymphocyte |2 NLM | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 700 | 1 | |a Zhang, Boyang |e verfasserin |4 aut | |
| 700 | 1 | |a Woldemeskel, Bezawit A |e verfasserin |4 aut | |
| 700 | 1 | |a Garliss, Caroline C |e verfasserin |4 aut | |
| 700 | 1 | |a Cheung, Laurene S |e verfasserin |4 aut | |
| 700 | 1 | |a Choudhury, Dilshad |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiajia |e verfasserin |4 aut | |
| 700 | 1 | |a Aparicio, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Bom, Sadhana |e verfasserin |4 aut | |
| 700 | 1 | |a Rashid, Rufiaat |e verfasserin |4 aut | |
| 700 | 1 | |a Caushi, Justina X |e verfasserin |4 aut | |
| 700 | 1 | |a Hsiue, Emily Han-Chung |e verfasserin |4 aut | |
| 700 | 1 | |a Cascino, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Kwaa, Abena K |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Dipika |e verfasserin |4 aut | |
| 700 | 1 | |a Thapa, Sampriti |e verfasserin |4 aut | |
| 700 | 1 | |a Ordonez, Alvaro A |e verfasserin |4 aut | |
| 700 | 1 | |a Pekosz, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a D'Alessio, Franco R |e verfasserin |4 aut | |
| 700 | 1 | |a Powell, Jonathan D |e verfasserin |4 aut | |
| 700 | 1 | |a Yegnasubramanian, Srinivasan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Shibin |e verfasserin |4 aut | |
| 700 | 1 | |a Pardoll, Drew M |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Hongkai |e verfasserin |4 aut | |
| 700 | 1 | |a Cox, Andrea L |e verfasserin |4 aut | |
| 700 | 1 | |a Blankson, Joel N |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Kellie N |e verfasserin |4 aut | |
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