Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664818 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12685790.fastq.gz | Fastqsanger.gz |
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Project description:AS TCR related antibody Fab fragment was selected on a HLA-A2 peptide library displayed on yeast for cross-reactivity check
2022-10-09 | GSE215018 | GEO
Project description:Carbamazepine (CBZ) can cause severe cutaneous adverse reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, and is strongly associated with HLA risk alleles. However, HLA genotype alone incompletely predicts clinical risk. Adverse drug reactions depend on drug-peptide-HLA conformation, immunoregulatory cell interactions and the presence of drug-specific TCR clonotypes in susceptible patients. An unresolved question is whether patients that develop a specific drug reaction harbor the same drug-specific TCR (public TCR) or generate patient unique TCRs (private TCR). To address this controversy we expressed four published CBZ-associated TCRs including two public and two private clonotypes, in TCR-null TG40 cells and tested activation using monoallelic 721.221 APCs expressing HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, or HLA-B*58:01(TE→MA), as well as HLA-transgenic/MHC I-deficient murine splenic APCs. T-cell activation was quantified by PD-1, CD69, and 4-1BB, while LC-MS/MS immunopeptidomics/MAPPs was used to assess drug effects on the peptide repertoire. CBZ docking was applied to define drug-peptide-MHC-TCR interactions in a drug reactive peptide specific TCR. Public TCRs showed no CBZ-dependent activation, whereas private TCRs displayed dose-dependent, HLA class I-dependent responses supported by HLAB*15:02 and unexpectedly HLA-B*57:01, but not HLA-B*58:01. Amino acid substitutions to HLA-B*58:01 (T45-E46 to M45-A46) mapped drug presentation to restore CBZ responsiveness without altering HLA expression. CBZ did not detectably induce broad abacavir-like peptide motif alterations but amplified HIV Gag KF11 peptide-driven T cell activation in an allele- andmutation-dependentmanner. Modeling predicted a candidate CBZ accessible region beneath the peptide near HLA Met67, HLA Tyr9, and a conserved CDR3a tyrosine providing a plausible structural rationale for allele and clonotype-dependent activation. These findings support a model in which CBZ potentiates binding of selected peptide-HLA-TCR interfaces governed by HLA cleft architecture and clonotype-level TCR sensitivity. This mechanismexplains why HLA screening alone incompletely predicts CBZ-SJS/ TEN risk and highlights peptide-HLA-TCR functional context as a potential determinant for improved risk assessment and mechanistic drug hypersensitivity testing.
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Project description:We introduced single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation that can be used for screening antigen specific CD8+ T cells. We compared the diversity of T cell receptor repertoire captured by SCT and folded peptide-MHC multimer presenting HLA-A02:01 restricted CMV peptide. We then constructed SCT libraries designed to capture SARS-CoV-2 spike specific CD8+ T cells from COVID-19 participants and healthy donors. TCR sequencing with antigen specificity was analyzed. The immunogenicity of these epitopes was validated by functional assays of T cells with cloned TCRs captured using SCT libraries.
2022-01-01 | E-MTAB-11229 | biostudies-arrayexpress
Project description:We identified epitopes derived from FOXM1 which were immunogenic on HLA-A*02:01, HLA-A*24:02, and HLA-A*23:01, endogenously-processed and presented, and resulted in T cell activation and cytotoxic T cell responses. Following the generation of TCR-T cells, sensitivity and specificity were confirmed by peptide dose-response and X-scan, respectively. Most importantly, adoptive transfer of TCR engineered T cells led to a significant reduction in tumor growth, as well as significantly prolonged survival in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) tumor-bearing murine model. Our studies confirm the immunogenicity of FOXM1 and feasibility of targeting this antigen using TCR-engineering.
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Project description:Few non-classical HLA-E restricted HIV-specific epitopes have been described, and even less is known about the functional profile of responding CD8 T cells (CD8s). This study evaluates the functional characteristics of CD8s targeting the Gag epitope (KAFSPEVIPMF or KF11) based on their restriction by either HLA-E (E-CD8s) or HLA-B57 (B57-CD8s). CD8s from 8 people with HIV (PWH) were cocultured with KF11 peptide presented by cell lines expressing HLA-B*57:01, HLA-E*01:01 or E*01:03. CD8s were analyzed through single-cell (sc) RNA and TCR sequencing. Additionally, supernatants were analyzed for soluble proteomics using a Luminex assay. B57-CD8s secreted higher levels of cytotoxic cytokines such as IFNγ, while E-CD8s produced more chemotactic cytokines, including RANTES, CXCL10 (IP-10), and IL27confirmed through scRNAseq. Despite distinct cytokine profiles, TCR clonotypes stimulated by KF11 were cross-restricted by HLA-B*57 and HLA-E*01/03. In vitro T cell reporter assays clearly demonstrated this cross-restriction. A TRAV5-containing metaclonotype cluster was seen in PWH with lower viral loads. These findings demonstrate that HIV-specific CD8s in PWH exhibit cross HLA-B*57 and HLA-E*01/03 restriction, resulting in functionally distinct immune responses that may contribute to HIV control.
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Project description:HLA-E molecules can present self and pathogen-derived peptides to both NK-cells and T-cells. T-cells that recognize HLA-E peptides via their T-cell receptor (TCR) are termed donor-unrestricted T-cells due to restricted allelic variation of HLA-E. The composition and repertoire of HLA-E TCRs is not known so far. We performed TCR sequencing on CD8+ T-cells from 21 individuals recognizing HLA-E tetramers (TM) folded with 2 Mtb HLA-E restricted peptides. We sorted HLA-E Mtb TM+ and TMCD8+ T-cells directly ex vivo and performed bulk RNA-sequencing and single cell TCR sequencing. The identified TCR repertoire was diverse and showed no conservation between and within individuals. TCRs selected from our single cell TCR sequencing data could be activated upon HLA-E/peptide stimulation, although not robust, reflecting potentially weak interactions between HLA-E peptide complexes and TCRs. Thus, HLA-E Mtb specific T-cells have a highly diverse TCR repertoire.
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