Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation.
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ABSTRACT:
SUBMITTER: Mijnheer G
PROVIDER: S-EPMC8113485 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe plasticity of monocytes enables them to exert multiple roles during an immune response, including promoting immune tolerance. How monocytes alter their functions to convey immune tolerance in the context of lower respiratory tract infections in humans is not well understood. Here, we sought to identify epigenetic and transcriptomic features of cytokine production capacity in circulating monocytes during community-acquired pneumonia (CAP).MethodsCirculating CD14+ monocytes were obtained from the blood of CAP patients included in a longitudinal, observational cohort study, on hospitalization (acute stage, n=75), and from the same patients after a 1-month follow-up (recovery stage, n=56). Age and sex-matched non-infectious participants were included as controls (n=41). Ex vivo cytokine production after lipopolysaccharide (LPS) exposure was assessed by multiplex assay. Transcriptomes of circulating monocytes were generated by RNA-sequencing, and DNA methylation levels in the same monocytes were measured by reduced representation bisulfite sequencing. Data were integrated by fitting projection-to-latent-structure models, and signatures derived by partial least squares discrimination.ResultsMonocytes captured during the acute stage exhibited impaired TNF, IL-1β, IL-6, and IL-10 production after ex vivo stimulation with LPS, relative to controls. IL-6 production was not resolved in recovery monocytes. Multivariate analysis of RNA-sequencing data identified 2938 significantly altered RNA transcripts in acute-stage monocytes (fold expression ≤-1.5 or ≥1.5; adjusted p ≤ 0.01), relative to controls. Comparing DNA methylation levels in circulating monocytes of CAP patients to controls revealed minimal differences, specifically in DNAse hypersensitive sites (HS) of acute-stage monocytes. Data integration identified a cholesterol biosynthesis gene signature and DNAse HS axis of IL-1β and IL-10 production (R2 =0.51).ConclusionsCirculating monocytes obtained from CAP patients during the acute stage exhibited impaired cytokine production capacities, indicative of reprogramming to a state of immune tolerance, which was not fully resolved after 1 month. Our split-sample study showed that 51% of the immune tolerance phenotype can be explained, at least in part, by coordinated shifts in cholesterol biosynthesis gene expression and DNAse HS methylation levels. A multi-scale model identified an epigenetic and transcriptomic signature of immune tolerance in monocytes, with implications for future interventions in immunosuppression.Trial registrationNCT number NCT02928367.
| S-EPMC8365568 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is an autoimmune disease affecting 1% of the world population and is characterized by chronic inflammation of the joints sometimes accompanied by extra-articular manifestations. K/BxN mice, originally described in 1996 as a model of polyarthritis, exhibit knee joint alterations. The aim of this study was to describe temporomandibular joint (TMJ) inflammation and damage in these mice. We used relevant imaging modalities, such as micro-magnetic resonance imaging (μMRI) and micro-computed tomography (μCT), as well as histology and immunofluorescence techniques to detect TMJ alterations in this mouse model. Histology and immunofluorescence for Col-I, Col-II, and aggrecan showed cartilage damage in the TMJ of K/BxN animals, which was also evidenced by μCT but was less pronounced than that seen in the knee joints. μMRI observations suggested an increased volume of the upper articular cavity, an indicator of an inflammatory process. Fibroblast-like synoviocytes (FLSs) isolated from the TMJ of K/BxN mice secreted inflammatory cytokines (IL-6 and IL-1β) and expressed degradative mediators such as matrix metalloproteinases (MMPs). K/BxN mice represent an attractive model for describing and investigating spontaneous damage to the TMJ, a painful disorder in humans with an etiology that is still poorly understood.
| S-EPMC7002582 | biostudies-literature
Project description:The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.
| S-EPMC7260038 | biostudies-literature
Project description:Regulatory T (Treg) cells mainly develop within the thymus and arise from CD25+Foxp3- (CD25+ TregP) or CD25-Foxp3+ (Foxp3+ TregP) Treg cell precursors resulting in Treg cells harboring distinct transcriptomic profiles and complementary T cell receptor repertoires. The stable and long-term expression of Foxp3 in Treg cells and their stable suppressive phenotype are controlled by the demethylation of Treg cell-specific epigenetic signature genes including an evolutionarily conserved CpG-rich element within the Foxp3 locus, the Treg-specific demethylated region (TSDR). Here we analyzed the dynamics of the imprinting of the Treg cell-specific epigenetic signature genes in thymic Treg cells. We could demonstrate that CD25+Foxp3+ Treg cells show a progressive demethylation of most signature genes during maturation within the thymus. Interestingly, a partial demethylation of several Treg cell-specific epigenetic signature genes was already observed in Foxp3+ TregP but not in CD25+ TregP. Furthermore, Foxp3+ TregP were very transient in nature and arose at a more mature developmental stage when compared to CD25+ TregP. When the two Treg cell precursors were cultured in presence of IL-2, a factor known to be critical for thymic Treg cell development, we observed a major impact of IL-2 on the demethylation of the TSDR with a more pronounced effect on Foxp3+ TregP. Together, these results suggest that the establishment of the Treg cell-specific hypomethylation pattern is a continuous process throughout thymic Treg cell development and that the two known Treg cell precursors display distinct dynamics for the imprinting of the Treg cell-specific epigenetic signature genes.
| S-EPMC6797672 | biostudies-literature
Project description:Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.
| S-EPMC6237229 | biostudies-literature
Project description:ObjectiveTregs are crucial for immune regulation, and environment-driven adaptation of effector (e)Tregs is essential for local functioning. However, the extent of human Treg heterogeneity in inflammatory settings is unclear.MethodsWe combined single-cell RNA- and TCR-sequencing on Tregs derived from three to six patients with juvenile idiopathic arthritis (JIA) to investigate the functional heterogeneity of human synovial fluid (SF)-derived Tregs from inflamed joints. Confirmation and suppressive function of the identified Treg clusters was assessed by flow cytometry.ResultsFour Treg clusters were identified; incoming, activated eTregs with either a dominant suppressive or cytotoxic profile, and GPR56+CD161+CXCL13+ Tregs. Pseudotime analysis showed differentiation towards either classical eTreg profiles or GPR56+CD161+CXCL13+ Tregs supported by TCR data. Despite its most differentiated phenotype, GPR56+CD161+CXCL13+ Tregs were shown to be suppressive. Furthermore, BATF was identified as an overarching eTreg regulator, with the novel Treg-associated regulon BHLHE40 driving differentiation towards GPR56+CD161+CXCL13+ Tregs, and JAZF1 towards classical eTregs.ConclusionOur study reveals a heterogeneous population of Tregs at the site of inflammation in JIA. SF Treg differentiate to a classical eTreg profile with a more dominant suppressive or cytotoxic profile that share a similar TCR repertoire, or towards GPR56+CD161+CXCL13+ Tregs with a more distinct TCR repertoire. Genes characterising GPR56+CD161+CXCL13+ Tregs were also mirrored in other T-cell subsets in both the tumor and the autoimmune setting. Finally, the identified key regulators driving SF Treg adaptation may be interesting targets for autoimmunity or tumor interventions.
| S-EPMC9525321 | biostudies-literature
Project description:FoxP3+ T regulatory (Treg) cells are central elements of immunologic tolerance. They are abundant in many tumors, where they restrict potentially favorable antitumor responses. We used a three-pronged strategy to identify genes related to the presence and function of Tregs in the tumor microenvironment. Gene expression profiles were generated from tumor-infiltrating Tregs (TITRs) of both human and mouse tumors and were compared with those of Tregs of lymphoid organs or normal tissues from the same individuals. A computational deconvolution of whole-tumor datasets from the Cancer Genome Atlas (TCGA) was performed to identify transcripts specifically associated with Tregs across thousands of tumors from different stages and locations. We identified a set of TITR-differential transcripts with striking reproducibility between tumor types in mice, between mice and humans, and between different human patients spanning tumor stages. Many of the TITR-preferential transcripts were shared with "tissue Tregs" residing in nonlymphoid tissues, but a tumor-preferential segment could be identified. Many of these TITR signature transcripts were confirmed by mining of TCGA datasets, which also brought forth transcript modules likely representing the parenchymal attraction of, or response to, tumor Tregs. Importantly, the TITR signature included several genes encoding effective targets of tumor immunotherapy. A number of other targets were validated by CRISPR-based gene inactivation in mouse Tregs. These results confirm the validity of the signature, generating a wealth of leads for understanding the role of Tregs in tumor progression and identifying potential targets for cancer immunotherapy.
| S-EPMC6233093 | biostudies-literature
Project description:Induction of immunosuppressive T-regulatory cells (Tregs) is a desirable goal in autoimmunity, and perhaps other immune diseases of activation. One promising avenue is with the bacille-calmette-guérin (BCG) vaccine in autoimmune type 1 diabetes (T1D). Its administration is associated with gradual clinical improvements in human autoimmunity over a 2-3 year post-vaccination period. We hypothesize that those improvements, and their unusually long time course to fully materialize, are partially attributable to BCG's induction of Tregs. Here we report on a 3 year-long longitudinal cohort of T1Ds and examine the mechanism by which Treg induction occurs. Using the Human Infinium Methylation EPIC Bead Chip, we show that BCG vaccination is associated with gradual demethylation of most of 11 signature genes expressed in highly potent Tregs: Foxp3, TNFRSF18, CD25, IKZF2, IKZF4, CTLA4, TNFR2, CD62L, Fas, CD45 and IL2; nine of these 11 genes, by year 3, became demethylated at the majority of CpG sites. The Foxp3 gene was studied in depth. At baseline Foxp3 was over-methylated compared to non-diabetic controls; 3 years after introduction of BCG, 17 of the Foxp3 gene's 22 CpG sites became significantly demethylated including the critical TSDR region. Corresponding mRNA, Treg expansion and clinical improvement supported the significance of the epigenetic DNA changes. Taken together, the findings suggest that BCG has systemic impact on the T cells of the adaptive immune system, and restores immune balance through Treg induction.
| S-EPMC8298580 | biostudies-literature
Project description:Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve/activated/effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic/functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional/migratory impairments under aGVHD. The findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.
2021-05-27 | GSE175603 | GEO
Project description:Lately it has become possible to analyze transcriptomic profiles in tissue sections with retained cellular context. We aimed to explore synovial biopsies from rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients, using Spatial Transcriptomics (ST) as a proof of principle approach for unbiased mRNA studies at the site of inflammation in these chronic inflammatory diseases. Synovial tissue biopsies from affected joints were studied with ST. The transcriptome data was subjected to differential gene expression analysis (DEA), pathway analysis, immune cell type identification using Xcell analysis and validation with immunohistochemistry (IHC). The ST technology allows selective analyses on areas of interest, thus we analyzed morphologically distinct areas of mononuclear cell infiltrates. The top differentially expressed genes revealed an adaptive immune response profile and T-B cell interactions in RA, while in SpA, the profiles implicate functions associated with tissue repair. With spatially resolved gene expression data, overlaid on high-resolution histological images, we digitally portrayed pre-selected cell types in silico. The RA displayed an overrepresentation of central memory T cells, while in SpA effector memory T cells were most prominent. Consequently, ST allows for deeper understanding of cellular mechanisms and diversity in tissues from chronic inflammatory diseases.
| S-EPMC6908624 | biostudies-literature