Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells
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PROVIDER: PRJNA644579 | ENA |
REPOSITORIES: ENA
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Project description:The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was ‘exhausted’ or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.
2020-07-22 | GSE153931 | GEO
Project description:The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.
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Project description:Reactive astrocytes in ALS models display dysregulated intron retention
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Project description:Aiming to identify gene expression signatures underlying the pathogenesis of infertility, we performed global gene expression profiling on testis samples in patients with severely impaired and normal spermatogenesis.
2020-02-19 | GSE145467 | GEO
Project description:Reactive astrocytes are implicated in Amyotrophic Lateral Sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined astrocyte translatome sequencing (TRAP-seq) from a SOD1 mouse model, which revealed a significant number of transcripts with reduced IR in ALS are upregulated in translation. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. These results provide novel insights into the molecular factors controlling the reactive transformation of ALS astrocytes.
2021-10-25 | GSE160133 | GEO
Project description:Single cell ATAC sequencing of SIINFEKL-reactive immune cell from intracranial murine GL261-SIINFEKL tumors 20 days after inoculation. SIINFEKL-reactive T cells were sorted based on dextramer staining. We show that loss of major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion.
2023-01-11 | E-MTAB-12512 | biostudies-arrayexpress
Project description:Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human iPSC-derived astrocytes carrying VCP, C9orf72 and SOD1 ALS-causing mutations as well as astrocytes stimulated to undergo reactive transformation. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell-adhesion, stress-response, and immune-activation. We examined translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts with decreased IR. Using nucleo-cytoplasmic fractionation of VCP astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear-detained transcripts is associated with increased cytoplasmic expression of genes and proteins encoding regulators of reactivity - indicating nuclear-to-cytoplasmic translocation and translation of spliced reactivity-related transcripts. Our study provides important insights into the molecular regulation of reactive transformation of ALS astrocytes.
2021-09-09 | PXD022604 | Pride
Project description:Poor immune reconstitution following haematopoietic stem cell transplantation (HSCT) can cause unwanted and harmful sequelae in recipients with chronic cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying poor reconstitution, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8+ memory lymphocytes from HCST recipients with different reconstitution efficiencies. Although the transcriptional and epigenomic signatures in non-reactive lymphocytes were not naïve or classic ‘exhaustion’ profiles, some gene expression was common to lymphocytes from other non-resolving infections. Reactive lymphocytes expressed higher levels of interferon/defence response and cell cycle genes in an interconnected network involving PI3KCG, STAT5B, NFAT, RBPJ, and NR3C1, increasing chromatin accessibility at the enhancer regions of immune and T cell receptor signalling pathway genes. We propose that increased HDAC6 expression in non-reactive lymphocytes decreases accessibility at particular enhancers including PI3KCG. Non-reactive cells also expressed higher levels of EGR and KLF factors that, along with lower expression of JARID2, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Together, transcription factors and chromatin modulators create a different chromatin accessibility landscape in reactive and non-reactive cells that not only affects immediate gene expression but differentially primes the cells for responses to additional signals.
2018-04-09 | GSE104750 | GEO
Project description:BACKGROUND:In the past 15?years, numerous studies have described aberrant DNA methylation of imprinted genes (e.g. MEST and H19) in sperm of oligozoospermic men, but the prevalence and genomic extent of abnormal methylation patterns have remained unknown. RESULTS:Using deep bisulfite sequencing (DBS), we screened swim-up sperm samples from 40 normozoospermic and 93 patients diagnosed as oligoasthenoteratozoospermic, oligoteratozoospermic or oligozoospermic, which are termed OATs throughout the manuscript, for H19 and MEST methylation. Based on this screening, we defined three patient groups: normal controls (NC), abnormally methylated oligozoospermic (AMO; n = 7) and normally methylated oligozoospermic (NMO; n = 86). Whole-genome bisulfite sequencing (WGBS) of five NC and five AMO samples revealed abnormal methylation levels of all 50 imprinting control regions in each AMO sample. To investigate whether this finding reflected epigenetic germline mosaicism or the presence of residual somatic DNA, we made a genome-wide inventory of soma-germ cell-specific DNA methylation. We found that > 2000 germ cell-specific genes are promoter-methylated in blood and that AMO samples had abnormal methylation levels at these genes, consistent with the presence of somatic cell DNA. The comparison between the five NC and six NMO samples revealed 19 differentially methylated regions (DMRs), none of which could be validated in an independent cohort of 40 men. Previous studies reported a higher incidence of epimutations at single CpG sites in the CTCF-binding region 6 of H19 in infertile patients. DBS analysis of this locus, however, revealed an association between DNA methylation levels and genotype (rs2071094), but not fertility phenotype. CONCLUSIONS:Our results suggest that somatic DNA contamination and genetic variation confound methylation studies in sperm of infertile men. While we cannot exclude the existence of rare patients with slightly abnormal sperm methylation at non-recurrent CpG sites, the prevalence of aberrant methylation in swim-up purified sperm of infertile men has likely been overestimated, which is reassuring for patients undergoing assisted reproduction.
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