Commensal bacteria promote type I interferon signaling to maintain immune tolerance in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE248021 | GEO | 2023/12/05
REPOSITORIES: GEO
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2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress
Project description:Commensal intestinal bacteria play key roles in regulating cells mediating immune tolerance; however, bacterial strains and related metabolites directly involved in this regulation are largely unknown. Here, using a mouse model of dextran sulfate sodium (DSS)-induced colitis combined with different antibiotic treatment, Enterobacter ludwigii, abundant in microbiota of mice treated with metronidazole, was screened out to have prophylactic and therapeutic effects on DSS-induced colitis with or without the presence of complex intestinal bacteria. E. ludwigii was demonstrated to induce CD103+DC and Treg-mediated immune tolerance for colitis remission using in vitro and in vivo experiments. Moreover, choline, one of E. ludwigii metabolites, was identified to increase DCs’ immune tolerance to promote Treg differentiation. E. ludwigii was found to induce DCs’ immune tolerance ability for Treg differentiation through choline and α7nAChR-mediated RA and TGF-β upregulation, resulting in protecting mice against DSS-induced colitis. This study provides potential therapeutic approaches for IBD.
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Project description:Regulatory T cells (Tregs) are immune cells that play a crucial role in maintaining tolerance to harmless antigens, including commensal microbes. In the intestine, Tregs can be classified into subsets based on their expression of transcription factors Helios, Rorg, Gata3 and cMaf. The exact functions of the intestinal Treg subsets and their role in maintaining tolerance to intestinal microbes is not fully understood. Here, we generated conditional knockout mice of each Treg subset and profiled the composition of their intestinal microbiota by performing 16S rRNA sequencing of stool from conditional knockouts and matched littermate controls.
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Project description:The colonic lamina propria contains a distinct population of Foxp3+ T regulatory cells (Tregs) that modulate responses to commensal microbes. Analysis of gene expression revealed that the transcriptome of colonic Tregs is distinct from splenic and other tissue Tregs. Rorγ and Helios in colonic Tregs mark distinct populations: Rorγ+Helios- or Rorγ-Helios+ Tregs. We uncovered an unanticipated role for Rorγ, a transcription factor generally considered to be antagonistic to Foxp3. Rorγ in colonic Tregs accounts for a small but specific part of the colon-specific Treg signature. Nrp1- Tregs were sorted from Foxp3-cre.Rorcfl/fl mice, which have a Treg-selective deletion of Rorc, or paired WT littermates. For low-input RNAseq, 1,000 TCRb+CD4+YFP(Foxp3)+Nrp1- cells were double-sorted into Trizol, RNA extracted and reverse-transcribed using ArrayScript (Ambion). To reduce variability at least three replicates were generated.
2015-07-25 | E-GEOD-71304 | biostudies-arrayexpress
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2015-07-25 | E-GEOD-68009 | biostudies-arrayexpress
Project description:The stability of FOXP3 expression in Tregs influences the balance between tolerance and autoimmunity. Treg cell development and function are regulated by IL-2, which binds to IL-2Rα (also called CD25). Decreased expression of CD25 (Il2ra gene) characterizes Tregs that lose FOXP3 expression (exTregs) and undergo transdifferentiation into TH17 cells. This has been established under arthritic conditions but whether this Treg transdifferenciation into exTregs occur following hypoxia exposure, it is unknown. Therefore, single-cell RNA-seq (10x Genomics) was performed using a 10X Genomics Chromium system to test the hypothesis that hypothesis that chronic hypoxia initiates Treg transcriptional reprogramming.
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Project description:Objectives. Immune homeostasis in the intestinal tract is tightly controlled by FOXP3+ regulatory T cells (Tregs), with loss of this Treg-mediated control linked to development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites strengthen intestinal Treg activity, leading to the notion that parasite-derived products could be harnessed and used as an immunoregulatory therapy for IBD. It has been previously demonstrated that the parasite Heligmosomoides polygyrus secretes a molecule (Hp-TGM) which mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. Our aim was to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach. Methods. Human CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or mammalian TGF-β. The induction of Tregs was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CTLA-4 and CD25. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was assessed by cellular co-culture suppression assays and secreted cytokines measured by cytometric bead array. Results. Hp-TGM efficiently induced FOXP3 expression (>60%), in addition to another Treg functional marker CTLA-4. Hp-TGM caused epigenetic modification of the FOXP3 loci to a greater extent than did TGF-β. Hp-TGM-induced Tregs also had superior suppressive function compared to TGF--induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Hp-TGM also induced a Treg phenotype in in vivo differentiated Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. Conclusion. These data indicate Hp-TGM has the potential to be used to generate stable human FOXP3+ Tregs to treat IBD.
2021-04-29 | GSE164548 | GEO
Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.
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Project description:Regulatory T (Treg) cells expressing the lineage-defining transcription factor Foxp3 are essential for the maintenance of immune tolerance. Foxp3 expression can be induced in a subset of developing self-reactive thymocytes to yield thymic Treg (tTreg) cells, critical for tolerance against self-antigens. Alternatively, activation of mature naïve T cells under non-inflammatory conditions can drive the differentiation of peripherally-induced Treg (pTreg) cells, thought to contribute to tolerance against commensal microbes and dietary antigens. While Foxp3 is indispensable for tTreg cell development and function, its role in pTreg cells has remained unknown. Here, we used a genetic fate mapping approach to characterize polyclonal pTreg cells induced by microbial colonization. We found that expression of a pTreg cell-specific gene expression program was initiated in the mesenteric lymph node (mLN) in a Foxp3-independent manner. Moreover, in contrast to Treg cells in secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of suppressing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 was required in a cell-intrinsic manner to limit IL-17 production and to prevent the expansion of intestinal mast cells. Our results suggest that, extrathymic Foxp3 induction likely acts as a mechanism to fine-tune the activity of Th17-like cells with Foxp3-independent regulatory functions.
2021-12-31 | GSE176235 | GEO