SARS-CoV-2 genome-wide mapping of CD8 T cell recognition reveals strong immunodominance and substantial CD8 T cell activation in COVID-19 patients

Abstract

To understand the CD8+ T cell immunity related to viral protection and disease severity in COVID-19, we evaluated the complete SARS-CoV-2 genome (3141 MHC-I binding peptides) to identify immunogenic T cell epitopes, and determine the level of CD8+ T cell involvement using DNA-barcoded peptide-major histocompatibility complex (pMHC) multimers. COVID-19 patients showed strong T cell responses, with up to 25% of all CD8+ lymphocytes specific to SARS-CoV-2-derived immunodominant epitopes, derived from ORF1 (open reading frame 1), ORF3, and Nucleocapsid (N) protein. A strong signature of T cell activation was observed in COVID-19 patients, while no T cell activation was seen in the 'non-exposed' and 'high exposure risk' healthy donors. Interestingly, patients with severe disease displayed the largest T cell populations with a strong activation profile. These results will have important implications for understanding the T cell immunity to SARS-CoV-2 infection, and how T cell immunity might influence disease development.

Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure

“…1b, Table S2). The immunodominant epitopes we discovered ex vivo were consistent with those measured by other means (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), but we also identified many epitopes with less dominant representation (yet observed with two or more reactive clonotypes), 188 of which had not been previously reported as minimal epitopes (Table S3). Importantly, CD8 + T cell reactivity to SARS-CoV-2 epitopes was observed across the entire proteome, generally distributed in a manner consistent with protein lengths (Table S4).…”

“…Several recent studies have focused on the discovery of relevant SARS-CoV-2 epitopes in both CD4 + and CD8 + T cell responses, leveraging in silico predictions, stimulation/expansion with peptide pools ( 8-18 ), and tetramer binding ( 19, 20 ). Collectively, these studies identified a number of immunodominant epitopes derived across the viral proteome including structural and non-structural proteins ( 8-20 ).…”

“…Several recent studies have focused on the discovery of relevant SARS-CoV-2 epitopes in both CD4 + and CD8 + T cell responses, leveraging in silico predictions, stimulation/expansion with peptide pools (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), and tetramer binding (19,20). Collectively, these studies identified a number of immunodominant epitopes derived across the viral proteome including structural and non-structural proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Interestingly, some of these specificities were also detected in uninfected individuals, suggesting potential cross-reactivity from endemic human coronaviruses (HCoV) to which the population is routinely exposed (21), though a direct connection to preexisting memory cells has not been established.…”

Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2

“…This study recognized a total of 122 immunogenic epitopes in SARS-CoV-2 infected patients among a total of 3141 epitopes. They also found that most immunodominant peptides are located in ORF1 and ORF3 of SARS-CoV-2 genome ( 143 ). These observations might help in understanding the quality of memory immune response especially considering that ORF1 is highly conserved among coronaviruses and there is baseline heterologous immunity against other coronaviruses in general population ( 143 ).…”

“…They also found that most immunodominant peptides are located in ORF1 and ORF3 of SARS-CoV-2 genome ( 143 ). These observations might help in understanding the quality of memory immune response especially considering that ORF1 is highly conserved among coronaviruses and there is baseline heterologous immunity against other coronaviruses in general population ( 143 ). Further, these antigens expand the horizon for vaccine design as it has been speculated that an increase in the number of epitopes may be beneficial in the generation of a more robust CD8+ T cell response ( 138 ).…”