Distal Ileum Transcriptomes of Mice with DSS-colitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183708 | GEO | 2021/09/09
REPOSITORIES: GEO
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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.
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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.
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Project description:Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype at mucosal surfaces where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IEC). IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response which protects from small intestinal inflammation. IEC ER stress causes expansion and activation of peritoneal B1b cells independent of microbiota and T cells that culminates in increased lamina propria and luminal IgA. Xbp1dIEC mice exhibit IEC ER stress by conditional deletion of X-box-binding protein 1 (XBP1). Here we examine differentially expressed genes in peritoneal B1b cells of germ-free Xbp1dIEC mice compared to littermate (WT) controls.
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Project description:We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin organization. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is pre-programmed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs. mRNA and accessible chromatin (DNase-seq) profiles from colonic and ileal IECs were compared between conventionally-raised (CR), germ-free (GF), and conventionalized (CV) C57BL/6 mice.
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