Unexposed individuals are fully equipped at the genetic level in terms of peptide coverage and T-cell repertoire against SARS-CoV-2: Analysis in a cohort of healthy donors and alloHSCT recipients

ABSTRACT

T-cell recognition of antigenic peptides presented by HLA molecules at the cell surface is critical for mounting an efficient adaptive immune response during acute viral infection such as COVID-19 caused by SARS-CoV-2. Recent data suggest that the depth of peptide coverage and the breadth of T cells that are able to respond are both important parameters associated with disease outcome. Strong T-cell responses against SARS-CoV-2 have also been reported in unexposed individuals, pointing to a possible role of heterologous immunity. In this study, we performed immunosequencing of the TCR CDR3beta region in a large cohort of 116 alloHSCT recipients and their corresponding healthy donors collected prior to the emergence of SARS-CoV-2. We used bioinformatics analyses and a large database of about 150,000 SARS-CoV-2 specific T-cell sequences in order to investigate the composition of the TCR repertoire regarding the presence of SARS-CoV-2 specific clonotypes in unexposed subjects among the more than 3.5 million CDR3beta sequences that we retrieved by immunosequencing. We also performed peptide binding predictions based on the reference proteome of the virus and by using the HLA class I high resolution typing data of the 116 patients. We could show that every individual is equipped with a large and diverse repertoire of clonotypes sharing their CDR3beta sequence with a SARS-CoV-2 specific T cell. Furthermore, the composition of the anti-SARSCoV- 2 repertoire was very similar among individuals, in healthy donors but also in the context of immune reconstitution in recipients, despite significant differences previously reported when accounting for the whole repertoire or for CMV-specific clonotypes only. In addition, each individual had the potential to cover a diverse repertoire of SARS-CoV-2 derived peptides (i.e., a few thousands strong and weak binders), but, interestingly, some interindividual differences were observed when only accounting for a strong affinity level of binding.