Journal Article

Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses

Zhang, Boyang, Kwaa, Abena K., Thapa, Sampriti, Pardoll, Drew M., Smith, Kellie N., Pekosz, Andrew, Aparicio, Luis, Thompson, Elizabeth A., Ji, Hongkai, Blankson, Joel N., Woldemeskel, Bezawit A., Bom, Sadhana, Zhang, Jiajia, Garliss, Caroline C., Ordonez, Alvaro A., D’Alessio, Franco R., Zhou, Shibin, Hsiue, Emily Han-Chung, Dykema, Arbor G., Choudhury, Dilshad, Rashid, Rufiaat, Caushi, Justina X., Yegnasubramanian, Srinivasan, Powell, Jonathan D., Singh, Dipika, Cox, Andrea L., Cheung, Laurene S., Cascino, Katherine

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Aged / Allergies / Antigens / Avidity / Biomedical research / Cancer immunotherapy / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / Cell proliferation / Clinical outcomes / Common cold / Coronaviridae / Coronaviruses / COVID-19 / COVID-19 - immunology / Cross Reactions / Disease / Epitopes, T-Lymphocyte - immunology / Female / Funding / Glycoproteins / Humans / Hypotheses / Immune imprinting / Immunologic Memory / Immunological memory / Immunotherapy / Infections / Infectious diseases / Jurkat Cells / Ligands / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Male / Memory cells / Middle Aged / Pandemics / Peptides / Proteins / Receptors, Antigen, T-Cell - immunology / SARS-CoV-2 - immunology / Severe acute respiratory syndrome coronavirus 2 / T cell receptors / Transfection / Viruses