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

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

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 cross-recognition by T-cells specific for common cold coronaviruses (CCCs). True T-cell cross-reactivity, 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 ViraFEST platform to identify T cell responses cross-reactive 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 cross-reactivity and assessments of functional avidity were performed using a TCR cloning and transfection system. RESULTS Memory CD4+ T-cell clonotypes that cross-recognized 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. Cross-reactive T-cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to mono-specific CD4+ T-cells, which was consistent with lower functional avidity of their TCRs for SARS CoV-2 relative to CCC. CONCLUSIONS For the first time, our data confirm the existence of unique memory CD4+ T cell clonotypes cross-recognizing SARS-CoV-2 and CCCs. The lower avidity of cross-reactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that pre-existing CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these cross-reactive T-cell responses impact clinical outcomes in COVID-19 patients.