HLA-dependent variation in SARS-CoV-2 CD8+ T cell cross-reactivity with human coronaviruses

Abstract

Pre-existing T cell immunity to SARS-CoV-2 in individuals without prior exposure to SARS-CoV-2 has been reported in several studies. While emerging evidence hints toward prior exposure to common-cold human coronaviruses (HCoV), the extent of- and conditions for- cross-protective immunity between SARS-CoV-2 and HCoVs remain open. Here, by leveraging a comprehensive pool of publicly available functionally evaluated SARS-CoV-2 peptides, we report 126 immunogenic SARS-CoV-2 peptides with high sequence similarity to 285 MHC-presented target peptides from at least one of four HCoV, thus providing a map describing the landscape of SARS-CoV-2 shared and private immunogenic peptides with functionally validated T cell responses. Using this map, we show that while SARS-CoV-2 immunogenic peptides in general exhibit higher level of dissimilarity to both self-proteome and -microbiomes, there exist several SARS-CoV-2 immunogenic peptides with high similarity to various human protein coding genes, some of which have been reported to have elevated expression in severe COVID-19 patients. We then combine our map with a SARS-CoV-2-specific TCR repertoire data from COVID-19 patients and healthy controls and show that whereas the public repertoire for the majority of convalescent patients are dominated by TCRs cognate to private SARS-CoV-2 peptides, for a subset of patients, more than 50% of their public repertoires that show reactivity to SARS-CoV-2, consist of TCRs cognate to shared SARS-CoV-2-HCoV peptides. Further analyses suggest that the skewed distribution of TCRs cognate to shared and private peptides in COVID-19 patients is likely to be HLA-dependent. Finally, by utilising the global prevalence of HLA alleles, we provide 10 peptides with known cognate TCRs that are conserved across SARS-CoV-2 and multiple human coronaviruses and are predicted to be recognised by a high proportion of the global population. Overall, our work indicates the potential for HCoV-SARS-CoV-2 reactive CD8+ T cells, which is likely dependent on differences in HLA-coding genes among individuals. These findings may have important implications for COVID-19 heterogeneity and vaccine-induced immune responses as well as robustness of immunity to SARS-CoV-2 and its variants.

Immunoinformatics Analysis of SARS-CoV-2 ORF1ab Polyproteins to Identify Promiscuous and Highly Conserved T-Cell Epitopes to Formulate Vaccine for Indonesia and the World Population

“…NetCTLpan analysis of these human peptides showed that these self-peptides were predicted as T-cell epitopes with similar binding affinity to the HLA molecules that present the corresponding SARS-CoV-2 peptide (Table 7 compare with Table 4). SARS-CoV-2 peptides having high similarity to several human proteins have also been reported by other [63].…”

Evaluating performance of existing computational models in predicting CD8+ T cell pathogenic epitopes and cancer neoantigens

“…A unique and valuable characteristic of this data megapool is that—with the exception of several peptides from other coronaviruses (e.g. MERS, SARS-CoV) which share homology with SARS-CoV-2 [ 27 , 28 ]—many of these peptides have not been used in the training data of the models under investigation ( Supplementary Fig. S1A available online at http://bib.oxfordjournals.org/ ) due to their recent identification.…”

Lack of association between HLA and asymptomatic SARS-CoV-2 infection

“…15 Centre d'Investigation Clinique, INSERM CIC 1403, Centre Hospitalo universitaire de Lille, Lille, France. 16 INSERM UMR 1219, Bordeaux, France. 17 CHU Lille, Lille, France.…”

“…Moreover, more than 100 immunogenic SARS-CoV-2 peptides are highly similar to peptides from at least one human coronavirus (hCoV) presented by a wide range of classical HLA molecules 16 . We, therefore, tested the hypothesis of an association between HLA alleles and asymptomatic SARS-CoV-2 infection in two large independent cohorts.…”