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 - 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
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
M1 - e146922
ER -