Single-cell RNA Sequencing reveals the expansion of Cytotoxic CD4+ T lymphocytes and the heterogeneity of pathogenesis in primary Sjögren’s syndrome patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE157278 | GEO | 2021/01/15
REPOSITORIES: GEO
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Project description:Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. We also measured the impact of pharmacologically inhibiting mitochondrial translation by performing Quantitative DIA proteomics on IL2 maintained or TCR retriggered CTL treated with the mitochondrial translation inhibitor doxycycline for 4.5 hrs. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.
2022-06-09 | PXD026948 | Pride
Project description:Effector cytotoxic T lymphocytes (CTLs) are critical for ridding the body of infected or cancerous cells. Recognition of an antigenic ligand by the CTL’s T cell receptor (TCR) triggers a signalling cascade that ultimately results in the targeted release of cytolytic granules and/or secretion of cytokines and chemokines to alert and recruit additional immune cells. These signalling cascades are capable of initiating transcription, translation, and cytoskeletal rearrangements. While previous work has demonstrated how translation and intracellular reorganisation contribute to CTL effector responses, the role of transcription is less well studied. To address this, we examined the impact of blocking transcription on the CTL proteome during TCR stimulation. These data demonstrated a strong transcriptional requirement for expression of cytokines and chemokines but not cytolytic molecules. Together with functional studies, these data reveal differential molecular control of the cell-cell communication and cytolytic functions of effector CTLs. CTLs exhibit complete and persistent priming for cytolytic activity prior to target cell encounter, but they require de novo transcription to recruit additional immune cells that amplify the response.
2023-10-16 | PXD034920 | Pride
Project description:Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.
2022-06-09 | PXD021508 | Pride
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that Myd88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which Myd88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, aged-associated B cells (ABCs) were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of the ABC subset in pSS.
2022-09-01 | GSE212467 | GEO
Project description:We found that MC38 tumor-conditioned medium(TCM) treatment significantly impacted multiple pathways including cholesterol metabolism pathway of CTLs. Further analysis of cholesterol metabolism pathway, we observed that Cholesterol-25-hydroxylase(Ch25h) expression was significantly downregulated after treated with TCM compared to treated with fibroblasted-conditioned medium(FCM). In the meanwhile, we found that activating transcription fator 3(Atf3) was signifcantly upregulated after TCM treatment. Finally, we investigated the Atf3-Ch25h axis regulating CTLs function in tumor context.
2023-09-21 | GSE190702 | GEO
Project description:Objective Neutrophils and aberrant NETosis have been implicated in the pathogenesis of diverse autoimmune diseases, however, their roles in primary Sjögren’s syndrome (pSS) remain unclear. We aimed to reveal the potential roles of neutrophils and neutrophil extracellular traps (NETs) in this study. Methods pSS patients were enrolled according to the corresponding diagnostic criteria. NETosis markers were measured in plasma and small salivary gland using ELISA and immunofluorescence. The gene signatures of neutrophils were assessed by RNA-Seq and RT-PCR. Reactive oxygen species (ROS), mitochondrial ROS (mitoROS) production and JC-1 was measured by flow cytometry. Results NETosis markers including cell free-DNA (cf-DNA), myeloperoxidase (MPO) in plasma and small salivary gland from pSS patients were significantly higher than healthy controls (HCs) and were associated with disease activity. RNA sequencing and RT-qPCR revealed activated Type I IFN signaling pathway and higher expression of type I interferon related genes in pSS neutrophils. Further stimulating with IFN-α 2a in vitro significantly induced ROS production and JC-1 monomer percentage in pSS neutrophils. Conclusions Our data suggest the involvement of neutrophils and enhanced NETosis in pSS patients. Further mechanism study in vitro revealed that type I IFN activation in pSS neutrophils led to mitochondrial damage and related ROS production which finally result in the generation of NETs.
2022-01-25 | GSE194234 | GEO
Project description:We investigated transcriptional changes in MAZR-, Runx3- and MAZR/Runx3-deficient cytotoxic T lymphocytes (CTLs). This analysis revealed that MAZR plays a compensatory role in the Runx3-dependent transcriptional program of CTL differentiation.
2021-03-11 | GSE129772 | GEO
Project description:We wished to examine early transcriptional changes that occur after TCR engagement in CD8+ cytotoxic T lymphocytes (CTLs). To this end, we differentiated effector CTLs from OTI TCR transgenic mice for 7 days in vitro and then stimulated them with anti-CD3 for various times before lysing for RNA-seq. Results demonstrated significant transcriptional changes starting from 20 minutes. After 60 minutes, upregulated genes were most enriched for cytokines and transcriptional machinery.
2023-10-15 | E-MTAB-12083 | biostudies-arrayexpress
Project description:Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by exocrine glands damage and extraglandular manifestations. To identify potential biomarkers for the early diagnosis of pSS and further investigate the potential mechanisms in progression of the disease, we combined our previous RNA- sequencing study and four microarrays data to conduct integrative transcriptome analyses in salivary glands (SGs) between the pSS and non-pSS. Differential gene expression analysis, gene co-expression network analysis and pathway analysis were conducted to detect hub gene, which was subsequently validated in peripheral blood. Correlation analysis, single-gene Gene Set Enrichment Analysis (GSEA) and receiver operating characteristic (ROC) curve were applied to investigate the role of ICOS in pSS and its classification capacity for pSS.
2020-12-22 | GSE159574 | GEO
Project description:Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Here we use Affymetrix U133 plus 2.0 microarray gene expression data from human parotid tissue. Parotid gland tissues were harvested from 17 pSS and 14 14 non-pSS sicca patients and 18 controls. The data were used in the following article: Nazmul-Hossain ANM, Pollard RPE, Kroese FGM, Vissink A, Kallenberg CGM, Spijkervet FKL, Bootsma H, Michie SA, Gorr SU, Peck AB, Cai C, Zhou H, Horvath S, Wong DTW (2012) Systems Analysis of Primary Sjögren’s Syndrome Pathogenesis in Salivary Glands: Comparative Pathways and Molecular Events in Humans and a Mouse Model. Parotid gland tissues were harvested from 17 pSS and 14 non-pSS sicca patients and 18 controls.
2012-09-06 | E-GEOD-40611 | biostudies-arrayexpress