{"doi":"10.1172/jci146922","title":"Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses","abstract":"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.","journal":"Journal of Clinical Investigation","year":2021,"id":150506,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":92,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":497499,"name":"Boyang Zhang","orcid":"0000-0003-2210-3572","position":1,"is_corresponding":false},{"id":293628,"name":"Bezawit A. 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D’Alessio","orcid":"0000-0002-3728-0064","position":19,"is_corresponding":false},{"id":228375,"name":"Jonathan D. Powell","orcid":"0000-0002-0850-2852","position":20,"is_corresponding":false},{"id":263709,"name":"Srinivasan Yegnasubramanian","orcid":"0000-0003-0744-6606","position":21,"is_corresponding":false},{"id":62904,"name":"Shibin Zhou","orcid":"0000-0003-1941-4425","position":22,"is_corresponding":false},{"id":59439,"name":"Drew M. Pardoll","orcid":"0000-0001-6215-1013","position":23,"is_corresponding":false},{"id":233094,"name":"Hongkai Ji","orcid":"0000-0002-6480-0141","position":24,"is_corresponding":false},{"id":355240,"name":"Andrea L. Cox","orcid":"0000-0002-9331-2462","position":25,"is_corresponding":false},{"id":292101,"name":"Joel N. Blankson","orcid":"0000-0002-9683-8021","position":26,"is_corresponding":false},{"id":62880,"name":"Kellie N. Smith","orcid":"0000-0002-6295-8930","position":27,"is_corresponding":false},{"id":615681,"name":"Arbor G. 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