| Autor: |
Dykema AG; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Zhang B; Department of Biostatistics, School of Public Health., Woldemeskel BA; Department of Medicine, School of Medicine, and., Garliss CC; Department of Medicine, School of Medicine, and., Cheung LS; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Choudhury D; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Zhang J; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Aparicio L; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Bom S; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Rashid R; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Caushi JX; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Hsiue EH; Sidney Kimmel Comprehensive Cancer Center.; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center., Cascino K; Department of Medicine, School of Medicine, and., Thompson EA; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Kwaa AK; Department of Medicine, School of Medicine, and., Singh D; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Thapa S; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Ordonez AA; Department of Pediatrics, School of Medicine, and., Pekosz A; Department of Molecular Microbiology and Immunology, School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA., D'Alessio FR; Department of Medicine, School of Medicine, and., Powell JD; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Yegnasubramanian S; Sidney Kimmel Comprehensive Cancer Center., Zhou S; Sidney Kimmel Comprehensive Cancer Center.; Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.; Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center., Pardoll DM; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center., Ji H; Department of Biostatistics, School of Public Health., Cox AL; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Department of Medicine, School of Medicine, and., Blankson JN; Department of Medicine, School of Medicine, and., Smith KN; Bloomberg~Kimmel Institute for Cancer Immunotherapy.; Sidney Kimmel Comprehensive Cancer Center. |
| Abstrakt: |
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. |
