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The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes

ABSTRACT: The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes

PROVIDER: PRJNA1066202 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27602600_1.fastq.gz	Fastqsanger.gz
	SRR27602600_2.fastq.gz	Fastqsanger.gz
	SRR27602601_1.fastq.gz	Fastqsanger.gz
	SRR27602601_2.fastq.gz	Fastqsanger.gz
	SRR27602602_1.fastq.gz	Fastqsanger.gz

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The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes

Project description:Non-mutated FVIII-specific CD4 T cell epitopes have been recently found to contribute to the development of inhibitors in patients with hemophilia A (HA), while auto-reactive CD4 T cells specific to FVIII circulate in the blood of healthy individuals at a frequency close to the foreign protein Ovalbumin. Thus, although FVIII is a self-protein, the central tolerance raised against FVIII appears to be low. In this study, we conducted a comprehensive analysis of the FVIII CD4 T cell repertoire in twenty-nine healthy donors. Sequencing of the CDR3β TCR region from isolated FVIII-specific CD4 T cells revealed a limited usage and pairing of TRBV and TRBJ genes, as well as a mostly hydrophobic composition of the CDR3β region according to their auto-reactivity. FVIII repertoire is dominated by a few clonotypes, with only 13 clonotypes accounting for half of the FVIII response. Through a large-scale epitope mapping of the full-length FVIII sequence, we identified 18 immunodominant epitopes located in the A1, A3, C1, and C2 domains and covering half of the T-cell response. These epitopes exhibited a broad specificity for HLA-DR or DP molecules or both. T-cell priming with this reduced set of peptides revealed that highly expanded clonotypes specific to these epitopes were responsible individually for up to 32% of the total FVIII repertoire. These FVIII T cell epitopes and clonotypes were shared among HLA-unrelated donors tested and previously reported HA patients. Our study highlights the role of the auto-reactive T cell response against FVIII in HA and its similarity to the response observed in healthy individuals. Thus, it provides valuable insights for the development of new tolerance induction and deimmunization strategies

2024-01-22 | GSE253521 | GEO

The self-reactive FVIII T cell repertoire in healthy individuals relies on a short set of epitopes and public clonotypes.

Project description:Non-mutated FVIII-specific CD4 T cell epitopes have been recently found to contribute to the development of inhibitors in patients with hemophilia A (HA), while auto-reactive CD4 T cells specific to FVIII circulate in the blood of healthy individuals at a frequency close to the foreign protein ovalbumin. Thus, although FVIII is a self-protein, the central tolerance raised against FVIII appears to be low. In this study, we conducted a comprehensive analysis of the FVIII CD4 T cell repertoire in 29 healthy donors. Sequencing of the CDR3β TCR region from isolated FVIII-specific CD4 T cells revealed a limited usage and pairing of TRBV and TRBJ genes as well as a mostly hydrophobic composition of the CDR3β region according to their auto-reactivity. The FVIII repertoire is dominated by a few clonotypes, with only 13 clonotypes accounting for half of the FVIII response. Through a large-scale epitope mapping of the full-length FVIII sequence, we identified 18 immunodominant epitopes located in the A1, A3, C1, and C2 domains and covering half of the T cell response. These epitopes exhibited a broad specificity for HLA-DR or DP molecules or both. T cell priming with this reduced set of peptides revealed that highly expanded clonotypes specific to these epitopes were responsible individually for up to 32% of the total FVIII repertoire. These FVIII T cell epitopes and clonotypes were shared among HLA-unrelated donors tested and previously reported HA patients. Our study highlights the role of the auto-reactive T cell response against FVIII in HA and its similarity to the response observed in healthy individuals. Thus, it provides valuable insights for the development of new tolerance induction and deimmunization strategies.

| S-EPMC10951066 | biostudies-literature

The endogenous antigen-specific CD8+ T cell repertoire is composed of unbiased and biased clonotypes with differential fate commitment.

Project description:Generating balanced populations of CD8+ effector and memory T cells is necessary for immediate and durable immunity to infections and cancer. Yet, a definitive understanding of how a diverse CD8+ T cell repertoire differentiates remains unclear. We identified several hundred TCR clonotypes that constitute the polyclonal response against a single antigen and found that a majority of TCR clonotypes were highly biased towards memory or effector fate. TCR-intrinsic biases were not stochastic and were dominant over environmental cues. Differential gene expression analysis of memory- or effector-biased TCR clonotypes showed bifurcation of differential fates at the early effector stage. Additionally, phylogenetic analysis revealed that memory-biased clonotypes retain their fate preferences in subclonal populations but effector-biased subclones can switch to memory fate. Our study highlights that the polyclonal CD8+ T cell response is a composite of unbiased and biased clonotypes with varying capacity to incorporate environmental cues in their cell fate decisions.

2025-02-27 | GSE241403 | GEO

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Project description:In a phase I clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain. However, the landscape of the B cell specificities and subsets induced by this vaccine remain undetermined. Here, we paired single cell RNA-sequencing and B cell receptor repertoire sequencing to analyze the relationship between transcriptome and B cell specificity following cHA immunization. We show that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell phenotype against two broadly neutralizing epitopes of the stalk domain. The overall specificities of the acute plasmablast and memory B cell responses were distinct, with the plasmablast compartment largely targeting non-neutralizing epitopes of the HA stalk. Altogether, these data indicate the B cell landscape following cHA vaccination includes diverse B cell subsets that are differentially induced by distinct vaccine formulations, including memory and de novo B cell responses against diverse broadly conserved epitopes.

2025-03-04 | GSE226633 | GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is generally refractory to immune checkpoint blockade, although patients with genetically unstable tumors can show modest therapeutic benefit. We previously demonstrated the presence of tumor-reactive CD8+ T cells in PDAC samples. Here, we charted the tumor-infiltrating T cell repertoire in PDAC by combining single-cell transcriptomics with functional testing of T cell receptors (TCRs) for reactivity against autologous tumor cells. On the basis of a comprehensive dataset including 93 tumor-reactive and 65 bystander TCR clonotypes, we delineated a gene signature that effectively distinguishes between these T cell subsets in PDAC, as well as in other tumor indications. This revealed a high frequency of tumor-reactive TCR clonotypes in three genetically unstable samples. In contrast, the T cell repertoire in six genetically stable PDAC tumors was largely dominated by bystander T cells. Nevertheless, multiple tumor-reactive TCRs were successfully identified in each of these samples, thereby providing a perspective for personalized immunotherapy in this treatment-resistant indication.

2024-01-26 | GSE254250 | GEO

Public T cell epitopes shared among SARS-CoV-2 Public T cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles variants are presented on prevalent HLA class I alleles

Project description:In this project, we used MS-based immunopeptidomics and T-cell screening assays to identify SARS-CoV-2 epitopes. The MS identified epitopes were further valdiated for CD8 T cell immunogenecity. PBMC from a large number of patients infected with SARS-CoV-2 were used for valdiation of MS identifed and predected CD 8 T cell epotipes.

2023-03-11 | PXD028862 | Pride

Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins

Project description:In a phase I clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single cell RNA-sequencing and B cell receptor repertoire sequencing. We have shown that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At one-year post-immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.

2025-03-04 | GSE260836 | GEO

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Project description:CD8+ T cells are key effectors in immune control of Trypanosoma cruzi infection. Within C57BL/6 mice, the T. cruzi-specific CD8+ T cell response is higly focused on several immunodominant epitopes including TSKb20. These immunodominant epitopes all elicit non-protective T cell responses that are entirely dispensable for immune control, suggesting that other, subdominant CD8+ T cells of unknown specificities might play an important role in mediating parasite control. We assessed the relative effector capacity of TSKb20 T cells compared to other responding T cells at the site of reinfection using paired scRNA and TCR sequencing to evaluate the gene expression profiles of particular T cell clonotypes.

2025-03-23 | GSE262370 | GEO

Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins II

2025-03-04 | GSE260941 | GEO

Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection.

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