Leveraging T-cell receptor – epitope recognition models to disentangle unique and cross-reactive T-cell response to SARS-CoV-2 during COVID-19 progression/resolution

ABSTRACT Despite the general agreement on the importance of T cells during SARS-CoV-2 infection, the clinical impact of specific and cross-reactive T-cell responses remains uncertain, while this knowledge may indicate how to adjust vaccines and maintain robust long-term protection against continuously emerging variants. To characterize CD8+ T-cell response to epitopes unique to SARS-CoV-2 (SC-unique) or shared with other coronaviruses (CoV-common), we trained a large number of TCR-epitope recognition models for MHC-I-presented SARS-CoV-2 epitopes from publicly available data. Applying those models to longitudinal COVID-19 TCR repertoires of critical and non-critical COVID-19 patients, we discovered that notwithstanding comparable CD8+ T-cell depletion and the sizes of putative CoV-common CD8+ TCR repertoires in all symptomatic patients at the initial stage of the disease, the temporal dynamics of putative SC2-unique TCRs differed depending on the disease severity. Only non-critical patients had developed large and diverse SC2-unique CD8+ T-cell response by the second week of the disease. Additionally, only this patient group demonstrated redundancy in CD8+ TCRs putatively recognizing unique and common SARS-CoV-2 epitopes. Our findings thus emphasize the role of the de novo CD8+ T-cell response and support the argument against the clinical benefit of pre-existing cross-reactive CD8+ T cells. Now, the analytical framework of this study can not only be employed to track specific and cross-reactive SARS-CoV-2 CD8+ T cells in any TCR repertoire but also be generalized to more epitopes and be employed for adaptive immune response assessment and monitoring to inform public health decisions.