[HTML][HTML] Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses
AG Dykema, B Zhang, BA Woldemeskel… - The Journal of …, 2021 - Am Soc Clin Investig
The Journal of clinical investigation, 2021•Am Soc Clin Investig
BACKGROUND Recent 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. METHODS We used the
viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses …
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. METHODS We used the
viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses …
BACKGROUND
Recent 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.
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.
The Journal of Clinical Investigation