Decidual-tissue resident memory T cells protect against nonprimary human cytomegalovirus infection at the maternal-fetal interface
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240976 | GEO | 2024/08/01
REPOSITORIES: GEO
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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.
2010-09-15 | E-GEOD-24151 | biostudies-arrayexpress
Project description:The latent human Cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune-compromised individuals, as well as burdens the immune system in immune-competent individuals. Though, T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in protection against the hCMV infection is lacking. Here we analyzed the single-cell transcriptomes and the single-cell T cell antigen receptor (TCR) repertoires of over 8000 hCMV-reactive peripheral T cells isolated from different memory compartments. The hCMV-reactive T cells were highly heterogeneous and consisted of different developmental memory and functional T cell subsets such as, the long-term memory precursors and effectors, T helper-17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs). The hCMV-antigen specific TREGs were enriched for molecules linked to their suppressive function and interferon response genes. The CTLs were of two types, the pre-effector and effector like. Of particular interest was the mixture of both CD4-CTLs and CD8-CTLs in both the pre-effector and effector cytotoxic clusters, suggesting that both CD4-CTLs and CD8-CTLs share transcriptomic signatures. The huge TCR clonal expansion of both the cytotoxic clusters imply their predominant role in protective immune response to CMV. Further the clonotype sharing between the CTL clusters and the long-term memory clusters, indicate potential progenitors of CD4-CTLs. Together our study has identified many subsets of hCMV-specific memory T cells that may have implication in better understanding the hCMV-specific T cell immunity to design vaccination strategies and therapeutics.
2024-03-20 | GSE235604 | GEO
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.
2010-09-16 | GSE24151 | GEO
Project description:In the present study, we aimed to discern the preconception decidual transcriptomic signature associated with in vivo defective decidualization in women who suffered sPE in a previous pregnancy. First, we performed a comparative global transcriptional profiling of endometrium from women who developed sPE in a previous pregnancy and from women who never have had sPE. Then, we selected those genes that were significantly deregulated 1.4-fold higher (FDR<0.05) and have an EntrezID code. As a result, we formulate a transcriptional signature associated with defective decidualization composed by 120 genes.
2021-10-06 | GSE172381 | GEO
Project description:CD8 tissue-resident memory T cells (TRM) provide frontline immunity in mucosal tissues. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are largely elusive. Here we identify an epitope-specific CD8 TRM population that is maintained by in situ MHC-I and B7 signaling following acute influenza infection. These TRM cells co-exhibit exhausted-like phenotypes and memory features, and provide heterologous immunity against secondary infection. PD-L1 blockade at the memory stage promotes exhausted-like TRM rejuvenation and secondary immunity at the cost of developing post-infection fibrotic sequelae. Increased numbers of CD8 TRM cells are observed in the lungs of pulmonary fibrosis patients compared to control patients. Thus, TRM exhaustion results from a tissue-specific cellular adaptation to balance fibrotic sequelae and secondary immunity.
2019-03-21 | GSE115786 | GEO
Project description:Reconstitution of cytomegalovirus (CMV)-specific immunity following transplant remains a primary clinical objective to prevent CMV disease, and adoptive immunotherapy of CMV-specific T cells can be an effective therapeutic approach. Due to the persistence of CMV, most CMV-specific CD8+ T cells become terminally differentiated effector cells (TEFF). However, a minor subset retains a memory phenotype (TM). Interestingly, recent studies suggest that CMV-specific CD8+ T cells with different phenotypes may have different abilities to reconstitute sustained immunity following transfer. The immunology of human CMV (HCMV) infections is reflected in the mouse model of MCMV infection. We found that HCMV- and MCMV-specific T cells displayed shared genetic programs, validating the MCMV model for studies of CMV-specific T cells in vivo. After transfer, the proliferative capacity of MCMV-specific TM cells was vastly superior to TEFF cells. Strikingly, TM cells expanded and established sustained and diverse T cell populations even after multiple challenges. Although both TEFF and TM cells could protect Rag-/- mice, only TM cells could consistently survive after transfer into immune replete, latently infected recipients and respond if recipient immunity was lost. These data show that CMV-specific TM cells retain memory function during persistent infection and can re-establish CMV immunity when necessary. C57BL/6 mice were infected intraperitoneally (i.p.) with MCMV strain MW97.01 between 6-16 weeks of age. Splenocytes were isolated from chronically-infected mice and co-stained with three PE-conjugated tetramers loaded with the antigenic peptides from M38, m139 and IE3, all of which promote memory inflation. Cells were then stained with fluorescently conjugated antibodies and sorted on a MoFlo cell sorter. Naïve CD8+ cells were identified as CD44lo. MCMV-specific T cells were identified as CD8+, CD44hi and tetramer binding and then further segregated into memory and effector cells subsets by their expression of KLRG1 and CD127.
2015-01-28 | E-GEOD-61927 | biostudies-arrayexpress
Project description:Influenza viruses (IV) infection is a public health concern worldwide. Currently, all available vaccines as well as antiviral drugs that target the virus itself are prone to resistance. Lessons learned from previous pandemic outbreaks is that people with a preexisting cellular immune response are either protected or developed less severe disease against the infection. Understanding CD8+ T cell immunity to IV across prominent HLA types is pivotal to rationally designing a universal influenza vaccine and generating protective immunity, especially for high-risk populations. Using mass spectroscopy, an immunopeptidomics analysis was carried out to characterize the entire landscape of peptides presented by MHC-I molecules post IV infection at different time points. We were able to identify sixteen naturally-presented MHC-I ligands restricted to different HLA allotypes including HLA-A*68, HLA-A*24, HLA-B*51, and HLA-B*07. Of these, nine peptides were immunogenic with multifunctional memory CD8 T cell response in different donors. These results highlight novel broadly protective IAV-derived CD8+ epitopes that reflect physiological peptide processing and presentation mechanisms that can work cooperatively with other distinct epitopes to provide optimal protection in particular against the newly-emerging variants.
2024-05-22 | PXD035241 | Pride
Project description:T cell receptor (TCR) signaling is a critical process in immunity to infectious disease and cancer. Recently, a genome-wide association study has implicated polymorphisms in the CISH locus with susceptibility to infectious diseases. However, the role of Cish in the immune responses and its molecular underpinnings remains unclear. Here we demonstrate that Cish deletion resulted in protection against viral infection and enhanced CD8+ T cell tumor immunity. Transcriptome profiling revealed a hyper-TCR activation signature in Cish-deficient CD8+ T cells. Subsequent analysis revealed an inhibitory role for Cish in PLCγ1 activation, ensuing Ca2+ release and downstream signaling. In the steady-state Cish was found to physically interact with PLCγ1, however, PLCγ1 was only found to be ubiquitinated after acute TCR stimulation in the presence of Cish. These data implicate Cish as a potent negative regulator of TCR signaling and T cell immunity to infection and cancer and may have significant clinical applications. 4 biological replicates from wild-type mice and 3 biological replicates from Cish knock-out (-/-) mice were analyzed.
2015-04-30 | E-GEOD-56328 | biostudies-arrayexpress
Project description:Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence in oxygen-deprived tissues of infection sites or tumors, the impact of local oxygen pressure on memory CD8+ T cells has remained largely unclear. We sought to elucidate how oxygen pressure impacted memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from an OXPHOS to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN- production capacity. Memory CD8+ T cells cultured under low oxygen pressure were able to persist long-term in vivo and provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions .
2022-12-01 | PXD032236 | Pride
Project description:Infection or reactivation with human cytomegalovirus (HCMV) is still a major cause of morbidity and mortality in patients undergoing solid organ transplantation or allogeneic stem cell transplantation (alloSCT). Recent studies have shown that protection against latent HCMV infection relies on a much broader antigen spectrum than previously expected. The identification of novel immunogenic HCMV-derived peptides that facilitate HCMV control is therefore essential to improve immune monitoring of HCMV-specific T cells and HCMV vaccine development. In particular, only a few HCMV-derived peptides have been described for less common HLA alleles, such as HLA-A*03:01 and HLA-B*15:01, limiting the implementation of these techniques for a substantial number of patients. Here, we identified novel HCMV-derived HLA-A*03:01- and HLA-B*15:01-restricted immunogenic peptides by an innovative combined in vitro and in silico approach. We utilized the computational tools Peptide-PRISM (1) and PRICE (2) to analyze mass spectrometric (MS) and ribosome sequencing (ribo-seq) datasets, respectively. To refine our in silico approach, we utilized machine learning to rate the identified peptide candidates based on their translational activity, binding affinity and positioning within the small open reading frames (sORFs), with the goal of assessing their likelihood to be presented on HLA-A*03:01 and HLA-B*15:01 molecules. After identifying the highest-scoring 49 canonical and 49 cryptic potentially immunogenic peptides for each HLA allele, we assessed their immunogenicity by screening HCMV-seropositive and -seronegative healthy donors, as well as alloSCT patients for their peptide-specific T-cell responses. We used a stimulation procedure in two consecutive steps: peripheral blood cells (PBMCs) were stimulated starting with peptide pools and subsequently with potentially reactive single peptides. In vitro T-cell stimulation resulted in the direct identification of three canonical and one cryptic HLA-A*03-restricted immunogenic peptides as well as five canonical and one cryptic HLA-B*15-restricted immunogenic peptide, with a specific IFNγ+/CD8+ T cell response of ≥ 0.02%. Highest T-cell responses were identified against two HLA-A*03-restricted and three HLA-B*15-restricted canonical peptides with up to 3.42% of IFNγ+/CD8+ T cells in patients 180 days post alloSCT. In conclusion, we identified specific T-cell responses against eight canonical and two cryptic HLA-A*03:01- and HLA-B*15:01-restricted peptides in healthy individuals and post-transplanted patients and which were classified as immunogenic. Of these, six peptides are novel HCMV-derived, immunogenic peptides according to the UniProt database, broadening the spectrum of immunogenic HCMV-derived peptides for personalized immune monitoring and vaccine development.
2024-06-16 | PXD043022 | Pride