COVID-19 Patients Form Memory CD8+ T Cells that Recognize a Small Set of Shared Immunodominant Epitopes in SARS-CoV-2
bioinformatics clinical immunology/immunity
Authors: Ferretti et al.
Journal/ Pre-Print:Medrxirv
Tags: Bioinformatics, Clinical, Immunology/Immunity
Research Highlights
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Mapping SARS-CoV-2 T cell epitopes presented by six of the most common Class I HLA types reveals that memory CD8+ T cells from recovered COVID-19 patient target a limited set of shared immunodominant epitopes (3-8 for each HLA type).
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These epitopes are not on high variable regions and are largely unique to SARS-CoV-2. Only 10% of those correspond to spike protein (only 3 of the 29 epitopes). This highlights the need to design vaccines that mimic natural CD8+ T cell responses and tempers enthusiasm related to potential cross-reactivity with common cold coronaviruses.
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Single-cell sequencing revealed that many different T cell clones target the same epitope, although it is the same TCR Va region that targets these epitopes.
Summary
Ferretti et al. performed an unbiased and detailed genome-wide screen (T-Scan) on memory CD8+ T cells against SARS-CoV-2 epitopes from 25 convalescent COVID-19 patients, focusing on epitopes presented by the most commonly expressed Class I HLA. SARS-CoV-2 CD8+ T cell memory establishment appears to be dominated by few antigenic epitopes that are shared among the same HLA type. Moreover, analysis of one specific HLA type (A*02:01) confirmed the presence of memory CD8+ T cells and revealed that many different T clonotypes target the same epitope. Specific fragments were recurrently recognised by the T cells of multiple patients that shared the same dominant TCR Va gene. The epitopes were compared to SARS-CoV-1 and common cold hCoV epitopes but found to be largely unique to SARS-CoV-2 and not on high variable regions. As many other studies have recently shown, only a small proportion (10%) of these epitopes correspond to the spike protein, highlighting the importance of the immune response against other parts of the virus such ORF1ab and N protein.
Impact for SARS-CoV2/COVID19 research efforts
Understand the precise targets of the CD8+ cellular immune response establishing immune memory and epitope specificity and frequency to SARS-CoV2/COVID19
Study Type
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Bioinformatics study
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Clinical Cohort study
Strengths and limitations of the paper
Novelty:
Comprehensive mapping of the COVID-19 convalescent CD8+T memory response by prevalent HLA types. Shows an oligoclonal response- with the same Va fragment- that largely targets a limited set of shared immunodominant epitopes.
Standing in the field:
Implications for vaccine development. In line with current literature for analysis of convalescent patients regarding immunodominance hierarchy (Griffoni et al. or Le Bert et al); and in contrast with in silico studies predicting epitopes presented by HLA alleles and other studies showing cross-reactivity to hCoV under different experimental setups
Appropriate statistics: The data are well presented and mostly descriptive but there are no statistical tests for significance.
Viral model used: Clinical samples of recovered COVID-19 patients
Translatability: This study does not aim for translatability per se but provides important information to help direct vaccine strategies. Moreover, there may be the potential for testing the presence of SARS-CoV2 specific memory CD8+ T cell IFNg secretion after ex vivo stimulation to identify previous infection.
Main limitations:
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While the study suggests that these specific epitopes are result in CD8+ T cell memory, this does not necessarily mean that they were the efficient effector clones during the immune response. It would be interesting to look at affinity for the recognised epitope.
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Statistics are not clearly shown.