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

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 common cold coronaviruses (CCCs) at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2–unexposed donors. 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.