Dataset Information

Resolving SARS-CoV-2 CD4⁺ T cell specificity via reverse epitope discovery.

ABSTRACT: The current strategy to detect immunodominant T cell responses focuses on the antigen, employing large peptide pools to screen for functional cell activation. However, these approaches are labor and sample intensive and scale poorly with increasing size of the pathogen peptidome. T cell receptors (TCRs) recognizing the same epitope frequently have highly similar sequences, and thus, the presence of large sequence similarity clusters in the TCR repertoire likely identify the most public and immunodominant responses. Here, we perform a meta-analysis of large, publicly available single-cell and bulk TCR datasets from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals to identify public CD4⁺ responses. We report more than 1,200 αβTCRs forming six prominent similarity clusters and validate histocompatibility leukocyte antigen (HLA) restriction and epitope specificity predictions for five clusters using transgenic T cell lines. Collectively, these data provide information on immunodominant CD4⁺ T cell responses to SARS-CoV-2 and demonstrate the utility of the reverse epitope discovery approach.

SUBMITTER: Pogorelyy MV

PROVIDER: S-EPMC9247234 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Resolving SARS-CoV-2 CD4<sup>+</sup> T cell specificity via reverse epitope discovery.

Pogorelyy Mikhail V MV Rosati Elisa E Minervina Anastasia A AA Mettelman Robert C RC Scheffold Alexander A Franke Andre A Bacher Petra P Thomas Paul G PG

Cell reports. Medicine 20220701 8

The current strategy to detect immunodominant T cell responses focuses on the antigen, employing large peptide pools to screen for functional cell activation. However, these approaches are labor and sample intensive and scale poorly with increasing size of the pathogen peptidome. T cell receptors (TCRs) recognizing the same epitope frequently have highly similar sequences, and thus, the presence of large sequence similarity clusters in the TCR repertoire likely identify the most public and immun ...[more]

PMID: 35841887

Similar Datasets

Project description:IntroductionThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the critical importance of understanding protective long-lasting immune responses. This study investigates the epitope specificity, T cell receptor (TCR) usage, and phenotypic changes in SARS-CoV-2-specfic CD8+ and CD4+ T cells over time in convalescent individuals with COVID-19.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from 28 unvaccinated individuals with primary SARS-CoV-2 infection (6 identified as the D614G variant, clade 20C) and analyzed up to 12 months post-symptom onset. Antigen-specific CD8+ and CD4+ T cells were analyzed using flow cytometry and single-cell RNA sequencing (scRNAseq) using specific dextramer and antibody reagents. TCR clonotypes and activation markers were characterized to explore T cell dynamics.ResultsSARS-CoV-2-specific CD8+ T cells exhibited waning frequencies long-term, transitioning from memory-like to a naïve-like state. scRNAseq revealed specificity against both spike and non-spike antigens with increased CD95 and CD127 expression over time, indicating that naïve-like T cells may represent stem cell memory T cells, which are multipotent and self-renewing, likely important for long-lived immunity. TCR clonal expansion was observed mainly in memory T cells, with overlapping TCR beta chain (TRB)-complementary determining region 3 (CDR3) sequences between participants, suggesting shared public TCR epitope-specific repertoires against SARS-CoV-2. Further, unique spike-specific CD4+ T cells with high CD95 and CD127 expression were identified, which may play a crucial role in long-term protection.DiscussionThis study highlights epitope-specificity heterogeneity, with some immunodominant responses, and suggests a potential role for long-lived SARS-CoV-2-specific T cell immunity. Shared TCR repertoires offers insights into cross-reactive and protective T cell clones, providing valuable information for optimizing vaccine strategies against emerging SARS-CoV-2 variants. The findings underscore the critical role of cellular immunity in long-term protection against SARS-CoV-2 and emphasizes the importance of understanding T cell dynamics.

Project description:BackgroundThe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is still a widespread concern. As one of the effective traditional Chinese medicine (TCM) formulae, Xuanfei Baidu formula (XFBD) shows significant efficacy for treatment of COVID-19 patients. However, its antiviral active compounds and mechanism are still unclear.PurposeIn this study, we explored the bioactive compounds of XFBD and its antiviral mechanism by integrating computational analysis and experimental testing.MethodsFocusing on the SARS-CoV-2 main protease (Mpro), as a key target in virus transcription and replication, the fluorescence resonance energy transfer (FRET) assay was built to screen out satisfactory natural inhibitors in XFBD. The surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) were undertaken to verify the binding affinity of ligand-Mpro. Omicron BA.1.1 and BA.2.3 variants were used to evaluate the antiviral activity of the focused compounds in non-cytotoxicity concentrations. For introducing the molecular mechanism, computational modeling and NMR spectra were employed to characterize the ligand-binding modes and identify the ligand-binding site on Mpro.ResultsFrom a library of 83 natural compounds, acteoside, licochalcone B, licochalcone D, linoleic acid, and physcion showed the satisfactory inhibition effects on Mpro with IC50 ranging from 1.93 to 42.96 µM, which were further verified by SPR. Showing the excellent binding affinity, acteoside was witnessed to gain valuable insights into the thermodynamic signatures by ITC and presented antiviral activity on Omicron BA.1.1 and BA.2.3 variants in vitro. The results revealed that acteoside inhibited Mpro via forming the hydrogen bond between 7-H of acteoside and Mpro.ConclusionActeoside is regarded as a representative active natural compound in XFBD to inhibit replication of SARS-CoV-2, which provides the antiviral evidence and some insights into the identification of SARS-CoV-2 Mpro natural inhibitors.

Dataset Information

Resolving SARS-CoV-2 CD4⁺ T cell specificity via reverse epitope discovery.

Publications

Resolving SARS-CoV-2 CD4<sup>+</sup> T cell specificity via reverse epitope discovery.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Resolving SARS-CoV-2 CD4+ T cell specificity via reverse epitope discovery.

Publications

Resolving SARS-CoV-2 CD4<sup>+</sup> T cell specificity via reverse epitope discovery.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Resolving SARS-CoV-2 CD4⁺ T cell specificity via reverse epitope discovery.