TY - JOUR
T1 - Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses
AU - Dykema, Arbor G.
AU - Zhang, Boyang
AU - Woldemeskel, Bezawit A.
AU - Garliss, Caroline C.
AU - Cheung, Laurene S.
AU - Choudhury, Dilshad
AU - Zhang, Jiajia
AU - Aparicio, Luis
AU - Bom, Sadhana
AU - Rashid, Rufiaat
AU - Caushi, Justina X.
AU - Hsiue, Emily Han Chung
AU - Cascino, Katherine
AU - Thompson, Elizabeth A.
AU - Kwaa, Abena K.
AU - Singh, Dipika
AU - Thapa, Sampriti
AU - Ordonez, Alvaro A.
AU - Pekosz, Andrew
AU - D’Alessio, Franco R.
AU - Powell, Jonathan D.
AU - Yegnasubramanian, Srinivasan
AU - Zhou, Shibin
AU - Pardoll, Drew M.
AU - Ji, Hongkai
AU - Cox, Andrea L.
AU - Blankson, Joel N.
AU - Smith, Kellie N.
N1 - Funding Information:
FUNDING. NIH 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.
Funding Information:
Authorship note: AGD and BZ contributed equally to this work. Conflict of interest: DMP and KNS have filed for patent protection on a subset of the technologies described herein (MANAFEST – A Novel Sensitive, Specific, Salable and Simple Method to Identify Functional Anti-Tumor T Cell Responses, US provisional patent application no. 62/407,820). AGD, ALC, FRD, DMP, JNB, and KNS have filed for patent protection on a subset of the technologies described herein (SARS-CoV-2-specific T cell receptors and Related Materials and Methods of Use, US provisional patent application no. 63/135,534). SZ is a founder of, holds equity in, and serves as a consultant to Personal Genome Diagnostics. SZ holds equity in Thrive Earlier Detection and has a research agreement with BioMed Valley Discoveries Inc. DMP reports stock and ownership interests in Aduro Biotech, DNAtrix, Dracen Pharmaceuticals, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, Potenza Therapeutics, RAPT, Tizona Therapeutics, Trieza Therapeutics, and WindMIL; a consulting or advisory role in Amgen, DNAtrix, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, Immunocore, Immunomic Therapeutics, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Merck, RAPT, and WindMIL; research grants from Compugen; patent royalties, and/or other intellectual property through their institution with Aduro Biotech, Arbor Pharmaceuticals, Bristol-Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL; and travel, accommodations, and expenses from Bristol-Myers Squibb and Five Prime Therapeutics. KNS receives commercial research funding from Bristol-Myers Squibb, AstraZeneca, and Enara Bio and has received travel support/honoraria from Illumina Inc. KNS, DMP, and SZ own founder’s equity in ManaT Bio. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. Copyright: © 2021, American Society for Clinical Investigation Submitted: December 15, 2020; Accepted: April 7, 2021; Published: April 8, 2021. Reference information: J Clin Invest. 2021;131(10):e146922. https://doi.org/10.1172/JCI146922.
Funding Information:
Funding for this work was provided by The Bloomberg~ Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, The Immune-Viral Landscape in COVID-19 Pneumonia-ARDS: IVAR study, The Bill and Melinda Gates Foundation (134582), NIH Cancer Center Support grant P30 CA006973, and NIH grants R37CA251447, U19A1088791, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U54CA260492. We would like to thank Bert Vogelstein and Kenneth W. Kinzler for helpful discussions and assistance with TCR cloning, Paul F. Robbins and Rami Yossef for help with TCR cloning, Jennifer Myers, Anuj Gupta, and the Experimental and Computational Genomics Core at the Sidney Kimmel Comprehensive Cancer Center for support with next-generation sequencing and preprocessing of 10x Genomics single cell 5′ VDJ data, the Sidney Kimmel Comprehensive Cancer Center FEST and TCR Immu-nogenomics Core Facility (FTIC) for support with ViraFEST assays and TCR sequencing, and Adaptive Biotechnologies for helpful discussions. Graphical abstract and study-time line images were created with BioRender.com. We thank our respective clinical, laboratory, and administrative teams as well as the patients and their families. The specimens utilized for this publication were part of the Johns Hopkins Biospecimen Repository, which relies on the contribution of many patients, research teams, and clinicians.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/5
Y1 - 2021/5
N2 - BACKGROUND. Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARSCoV-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. METHODS. We 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. RESULTS. Memory 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. CONCLUSIONS. Our 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. FUNDING. NIH 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.
AB - BACKGROUND. Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARSCoV-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. METHODS. We 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. RESULTS. Memory 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. CONCLUSIONS. Our 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. FUNDING. NIH 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.
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U2 - 10.1172/JCI146922
DO - 10.1172/JCI146922
M3 - Article
C2 - 33830946
AN - SCOPUS:85106666903
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
M1 - e146922
ER -