Antigen-specific T-cell receptor signatures of cytomegalovirus infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE114931 | GEO | 2018/11/21
REPOSITORIES: GEO
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Project description:<p>High-throughput linking of T cell receptor (TCR) sequences to their binding antigens is vital for immune profiling, yet challenging. We present Tetramer associated TCR Sequencing (TetTCR-Seq) to address this challenge. Binding is determined using a library of DNA-barcoded antigen tetramers that are rapidly and inexpensively generated using an in vitro transcription/translation platform. We included CMV+ donors (CMV seropositive donors who are infected with Cytomegalovirus) to screen for CMV specific TCRs.</p>
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Project description:The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. Together, these findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.
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Project description:Analysis of dendritic cells (DCs) at 6h and 48h after infection with cytomegalovirus (CMV) versus non infected. CMV tends to induce immunosuppression followed by lasting immunity. DCs appear to play a role in this effect. Results provide insights into CMV/DC interactions and suggest mechanisms for CMV-regulated early immune response. Keywords: gene expression array-based, count In the present study, immature monocyte-derived dendritic cells were generated from CMV neg healthy blood donors and infected or not with an endotheliotropic CMV strain. Gene expression modulation by the CMV infection was studied in a time course assay (non-infected - NI - vs 6h or 48h post-infection. Patient C has no 48h sample
2009-01-22 | E-GEOD-14490 | biostudies-arrayexpress
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Project description:CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human CMV (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-g–regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation. CD8+ T cells of naive, effector, and memory type were isolated from six latently chronic-infected healthy donors. For RNA isolation and microarray analysis, 3 independent donors and a pool of 3 additional healthy individuals were used. Total RNA of all naive CD8+ T cells was pooled and used as a common reference sample.
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Project description:A trimeric glycoprotein complex on the surface of human cytomegalovirus (CMV) binds to platelet-derived growth factor (PDGF) receptor α (PDGFRα) to mediate host cell recognition and fusion of the viral and cellular membranes. Soluble PDGFRα potently neutralizes CMV in tissue culture, and its potential use as an antiviral therapeutic has the benefit that any escape mutants will likely be attenuated. However, PDGFRα binds multiple PDGF ligands in the human body as part of developmental programs in embryogenesis and continuing through adulthood. Any therapies with soluble receptor therefore come with serious efficacy and safety concerns, especially for the treatment of congenital CMV. Soluble virus receptors that are orthogonal to human biology would reduce safety and efficacy concerns. This engineering problem is solved by deep mutational scanning on the D2-D3 domains of PDGFRα to identify variants that maintain interactions with the CMV glycoprotein trimer in the presence of competing PDGF ligands.
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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:Human fibroblast monolayers plated at a density of 3 x 104 cells/cm2 in 850 cm2 roller bottles were infected at confluency (day 5 post-seeding) with purified virions of human cytomegalovirus (CMV) strain AD169varATCC (AD) or the AD169 US27/US28 deletion mutant virus RV101 (RV) at a multiplicity of infection of 10. After virus adsorption for 1h at 37C with 5% CO2, the inoculum was removed and the cells were washed twice with culture medium prior to the addition of fresh medium. At 50, 72 and 98 hpi, infected monolayers were harvested, snap-frozen and stored at -80:C until the time course was completed. Uninfected confluent HF cultures were used as reference. mRNA was extracted using the FastTrack. 2.0 mRNA Isolation Kit (Invitrogen, Carlsbad, CA). Only RNA preparations reaching OD260/280 ratio values of 2.0 were used. Labeled cDNA populations were synthesized from 2 microg of mRNA per sample by reverse transcription and simultaneous incorporation of Cy3- (reference sample, green) or Cy5- (infected samples, red) dUTP using an oligo-dT20 primer and the Superscript II Reverse Transcriptase. Reference and sample cDNA populations were mixed and applied on the arrays. Hybridizations were performed at 650C for 16 to 18 h in a custom slide chamber with humidity maintained by a small reservoir of 3x SSC. The arrays were then washed, scanned with a Gene Pix 4000A Scanner, gridded and flagged with Gene Pix Pro 4.0 software before submission to the SMD. Groups of assays that are related as part of a time series. Computed
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