Ontology highlight
ABSTRACT:
PROVIDER: PRJNA416946 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8655490_1.fastq.gz | Fastqsanger.gz | |||
| SRR8655490_2.fastq.gz | Fastqsanger.gz | |||
| SRR8655491_1.fastq.gz | Fastqsanger.gz | |||
| SRR8655491_2.fastq.gz | Fastqsanger.gz | |||
| SRR8655492_1.fastq.gz | Fastqsanger.gz |
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Project description:c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis
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Project description:Foxp3+ regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. In peripheral tissues, Treg cells acquire enhanced suppressive functions and co-opt distinct transcriptional modules, allowing context and tissue-dependent immune regulation. Here we show that the transcription factor c-Maf was highly expressed by effector Treg cells and controlled their IL-10 production. In the intestine, c-Maf was required for the differentiation of RORgt+ microbiota-dependent Treg cells, and restricted their production of inflammatory cytokines. Consequently, Treg cell-specific loss of c-Maf resulted in perturbed intestinal homeostasis, microbial dysbiosis and a selective failure to control Th17 responses during homeostasis and upon chemically induced epithelial damage. Molecular profiling revealed that c-Maf regulated expression of key genes of the transcriptional signature of intestinal Treg cells, including Rorc and Il10. Thus, our study identifies a key role of c-Maf in preserving the identity and function of intestinal Treg cells, essential for the control of intestinal immune homeostasis.
2018-12-18 | GSE106396 | GEO
Project description:c-Maf-dependent regulatory T cell control of intestinal Th17 cells and immunoglobulin A establishes host-microbiota homeostasis
| PRJNA498200 | ENA
Project description:Th17 cells play a role as an inflammation mediator in a variety of autoimmune disorders, including inflammatory bowel disease (IBD) and thus are widely considered to be pathogenic. However, Th17 cells are present in the normal intestine and show a homeostatic phenotype, i.e., they participate in the maintenance of intestinal homeostasis rather than inducing inflammation. We observed an enlarged Th17 population in the small intestine of C57BL/6.IgA-/- mice compared to wild-type mice, which was further amplified with cholera toxin (CT) immunization without causing intestinal inflammation. The increased Th17 induction and the correspondingly 10-fold higher CTB-specific serum IgG response in C57BL/6.IgA-/- mice after CT immunization was microbiota dependent and was associated with increased segmented filamentous bacteria (SFB) in the small intestine of C57BL/6.IgA-/- mice. Oral administration of vancomycin greatly dampened both CT immunogenicity and adjuvanticity, and the differential CT responses in IgA-/- and wild-type mice disappeared after intestinal microbiota equalization. Using gnotobiotic mouse models, we found that CT induction of homeostatic intestinal Th17 responses was supported not only by SFB but also by other commensal bacteria. Furthermore, transcriptome analysis using IL-17AhCD2 reporter mice revealed a similar gene expression profile in CT-induced intestinal Th17 cells and endogenous intestinal Th17 cells at homeostasis, with upregulated expressions of a panel of immune regulatory genes, which was distinctly different from the gene expression profile of pathogenic Th17 cells. Taken together, we identified a non-pathogenic signature of intestinal homeostatic Th17 cells, which are actively regulated by the commensal microbiota and can be selectively stimulated by CT.
2017-08-31 | GSE97571 | GEO
Project description:T cells that express the transcription factor RORg, regulatory (Treg) or conventional (Th17), are strongly influenced by intestinal symbionts. In a genetic approach to mechanisms underlying this influence, we performed a screen for microbial genes implicated, in germfree mice monocolonized with E.coli Nissle. The loss of capsule-synthesis genes impaired clonal expansion and differentiation of intestinal RORg+ T cells. Mechanistic exploration revealed that the capsule-less mutants remained able to induce specific IgA and were highly IgA-coated. They could still trigger myeloid cells, and more effectively damaged epithelial cells in vitro. Unlike wild-type microbes, capsule-less mutants were mostly engulfed in intraluminal casts, large agglomerates composed of myeloid cells extravasated into the gut lumen. We speculate that sequestration in luminal casts of potentially harmful microbes reduces the immune system’s actual exposure, preserving host-microbe equilibrium. The variable immunostimulation by microbes charted in recent years may not solely be conditioned by triggering molecules or metabolites, but also by physical limits to immunocyte exposure.
2022-09-27 | GSE211049 | GEO
Project description:Intestinal epithelial cells (IEC) express large amounts of major histocompatibility complex II (MHCII) molecules. Despite this long-appreciated observation, the function of epithelial MHCII-mediated signaling on gut homeostasis remains enigmatic. As IECs serve as the primary cellular barrier between intestinal microbes and underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in tolerogenic responses towards the microbiota. Mice with an IEC-intrinsic defect in MHCII expression (IECΔMHCII) develop elevated T cell-dependent IgA responses, but a reduction in microbiota responsive regulatory T cells (Tregs). Despite elevated IgA levels in IECΔMHCII mice, immunoglobulin repertoires exhibit less selection and IgA has reduced reactivity to the microbiota, which is associated with increased inter-individual variability in microbiota composition. Consistent with reductions in microbiota-responsive Tregs, IECΔMHCII mice develop worsened colitis. A striking difference observed in the absence of IEC-MHCII is that while transcription of MHCII is similar, underlying mononuclear phagocytes had reduced surface MHCII. Macrophages were found to be capable of acquiring MHCII molecules from IECs, and macrophages isolated from IECΔMHCII mice had decreased capacity to stimulate Treg development. Thus, epithelial-myeloid interactions govern development of adaptive responses to microbial antigens within the gastrointestinal tract.
2021-09-09 | GSE183711 | GEO
Project description:Intestinal epithelial cells (IEC) express large amounts of major histocompatibility complex II (MHCII) molecules. Despite this long-appreciated observation, the function of epithelial MHCII-mediated signaling on gut homeostasis remains enigmatic. As IECs serve as the primary cellular barrier between intestinal microbes and underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in tolerogenic responses towards the microbiota. Mice with an IEC-intrinsic defect in MHCII expression (IECΔMHCII) develop elevated T cell-dependent IgA responses, but a reduction in microbiota responsive regulatory T cells (Tregs). Despite elevated IgA levels in IECΔMHCII mice, immunoglobulin repertoires exhibit less selection and IgA has reduced reactivity to the microbiota, which is associated with increased inter-individual variability in microbiota composition. Consistent with reductions in microbiota-responsive Tregs, IECΔMHCII mice develop worsened colitis. A striking difference observed in the absence of IEC-MHCII is that while transcription of MHCII is similar, underlying mononuclear phagocytes had reduced surface MHCII. Macrophages were found to be capable of acquiring MHCII molecules from IECs, and macrophages isolated from IECΔMHCII mice had decreased capacity to stimulate Treg development. Thus, epithelial-myeloid interactions govern development of adaptive responses to microbial antigens within the gastrointestinal tract.
2021-09-09 | GSE183710 | GEO
Project description:Intestinal epithelial cells (IEC) express large amounts of major histocompatibility complex II (MHCII) molecules. Despite this long-appreciated observation, the function of epithelial MHCII-mediated signaling on gut homeostasis remains enigmatic. As IECs serve as the primary cellular barrier between intestinal microbes and underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in tolerogenic responses towards the microbiota. Mice with an IEC-intrinsic defect in MHCII expression (IECΔMHCII) develop elevated T cell-dependent IgA responses, but a reduction in microbiota responsive regulatory T cells (Tregs). Despite elevated IgA levels in IECΔMHCII mice, immunoglobulin repertoires exhibit less selection and IgA has reduced reactivity to the microbiota, which is associated with increased inter-individual variability in microbiota composition. Consistent with reductions in microbiota-responsive Tregs, IECΔMHCII mice develop worsened colitis. A striking difference observed in the absence of IEC-MHCII is that while transcription of MHCII is similar, underlying mononuclear phagocytes had reduced surface MHCII. Macrophages were found to be capable of acquiring MHCII molecules from IECs, and macrophages isolated from IECΔMHCII mice had decreased capacity to stimulate Treg development. Thus, epithelial-myeloid interactions govern development of adaptive responses to microbial antigens within the gastrointestinal tract.
2021-09-09 | GSE183709 | GEO
Project description:Intestinal epithelial cells (IEC) express large amounts of major histocompatibility complex II (MHCII) molecules. Despite this long-appreciated observation, the function of epithelial MHCII-mediated signaling on gut homeostasis remains enigmatic. As IECs serve as the primary cellular barrier between intestinal microbes and underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in tolerogenic responses towards the microbiota. Mice with an IEC-intrinsic defect in MHCII expression (IECΔMHCII) develop elevated T cell-dependent IgA responses, but a reduction in microbiota responsive regulatory T cells (Tregs). Despite elevated IgA levels in IECΔMHCII mice, immunoglobulin repertoires exhibit less selection and IgA has reduced reactivity to the microbiota, which is associated with increased inter-individual variability in microbiota composition. Consistent with reductions in microbiota-responsive Tregs, IECΔMHCII mice develop worsened colitis. A striking difference observed in the absence of IEC-MHCII is that while transcription of MHCII is similar, underlying mononuclear phagocytes had reduced surface MHCII. Macrophages were found to be capable of acquiring MHCII molecules from IECs, and macrophages isolated from IECΔMHCII mice had decreased capacity to stimulate Treg development. Thus, epithelial-myeloid interactions govern development of adaptive responses to microbial antigens within the gastrointestinal tract.
2021-09-09 | GSE183708 | GEO
Project description:Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.
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