Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97184 | GEO | 2017/09/21
SECONDARY ACCESSION(S): PRJNA380919
REPOSITORIES: GEO
Similar Datasets
Project description:Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is trans-presented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα) and plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. When overproduced, IL-15 is a key driver of the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. To better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we performed quantitative proteomics of IL-15/Rα-stimulated murine IEL, sorted into their 3 main subpopulations, TCRγδ CD8αα, TCRαβ CD8αβ and TCRαβ CD8αα expressing IEL. The data reveal that high IL-15/Rα stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation.
2021-05-10 | PXD025891 | Pride
Project description:Intestinal intraepithelial T lymphocytes (T-IEL) patrol the single layer of epithelial cells lining the gut, and consist of both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, that are developmentally targeted to the intestine. To gain functional insights into these enigmatic cells, we used high-resolution quantitative mass spectrometry to investigate the proteomic landscape of the main T-IEL populations in the gut. Comparing the proteomes of induced T-IEL, tissue-resident memory TCRαβ+ CD8αβ+ cells and natural TCRγδ+ CD8αα+ and TCRαβ+ CD8αα+ T-IEL, with naive CD8+ T cells from lymph nodes reveals striking similarities between T-IEL subsets and the dominant effect of the gut environment on T-IEL phenotypes. Analysis of copy numbers/cell of >7000 proteins provides new understanding of the differences in composition of T cell antigen receptor signal transduction pathways in T-IEL versus conventional T cells and reveals skewing of the metabolic machinery towards an exhausted T cell phenotype adapted to the intestinal environment. This study provides a resource for exploring and understanding how multiple inputs are integrated into T-IEL function.
2021-03-15 | PXD023140 | Pride
Project description:The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here we show that AHRR is vital to sustain intestinal intraepithelial lymphocytes (IEL). Fewer IEL of all types were present in the absence of AHRR. Single cell RNA sequencing (scRNAseq) revealed an oxidative cell stress profile in Ahrr–/– IEL. Ahrr deficiency unleashed AHR-induced expression of CYP1A1, an oxidative enzyme that generates reactive oxygen species; this resulted in elevated intracellular content of reactive oxygen species, lipid peroxidation and ferroptosis in Ahrr–/– IEL. Dietary supplementation with selenium or Vitamin-E (Vit-E) to restore redox homeostasis rescued Ahrr–/– IEL. Loss of IEL in Ahrr deficient mice caused susceptibility to Clostridium difficile infection and dextran sodium sulfate-induced colitis. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IEL to preserve intestinal immune responses.
2023-01-19 | GSE199960 | GEO
Project description:Background: Tissue-resident gd intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vg TCR+ IELs, however, the mechanisms that control gd IEL maintenance within discrete intestinal segments are unclear. Btnl2, a member of Btnl family, has been shown to induce Treg differentiation and suppress T cell activation and proliferation in vitro. Btnl2 is highly enriched in villous IECs across different intestinal compartments and its expression is reported to be altered by inflammatory cues such as epithelial injury and tumor burden. We sought to understand the role of Btnl2 in regulating intestinal immune responses during homeostasis and inflammation and, particularly, in the induction and maintenance of intestinal gd IELs. Methods: We surveyed the gut immune system of in-house generated Btnl2-KO and WT mice within discrete intestinal segments (duodenum, jejunum, ileum, colon) during homeostasis and DSS-induced epithelial injury using flow cytometry, primary cell assays, immunoassays, and gene expression profiling. In addition, we performed high throughput transcriptomic (bulk RNAseq and scRNAseq) and TCR repertoire (scTCRseq) characterization of segment-specific Btnl2-KO and WT gd IELs at steady-state. Results: We characterized newly generated Btnl2 knockout mice and identify a role for Btnl2 in regulating the frequencies and phenotype of gd IELs preferentially in the ileum at steady state. We found that gd IELs derived from the ileum, but not duodenum, of Btnl2-KO mice possess a dysregulated antibacterial response module. By integrating RNA and single-cell TCR expression data we identified distinct transcriptional signatures and greater TCR repertoire diversity in ileal Btnl2-KO gd IELs. Upon DSS challenge, Btnl2-KO mice displayed enhanced colonic, but not ileal, intestinal inflammation and delayed mucosal repair. Conclusions: Collectively, our findings suggest that context-dependent Btnl2 expression fine-tunes intestinal immune responses to protect against epithelial injury. Overall, Btnl-mediated targeting of γδ IEL development and maintenance may help dissect their immunological functions in intestinal diseases with segment-specific manifestations.
2021-06-16 | GSE178273 | GEO
Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.
2023-10-20 | GSE220028 | GEO
Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.
2023-10-20 | GSE220022 | GEO
Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.
2023-10-20 | GSE220021 | GEO
Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.
2023-10-20 | GSE220020 | GEO
Project description:Intraepithelial lymphocytes (IELs) reside in the epithelial layer to protect against foreign pathogens and maintain epithelial barrier functions in the intestine. The interaction between IELs and epithelial cells is required for their functions; however, the underlying molecular machinery still remains to be elucidated. Here, we found that intestinal epithelium-specific deficiency in a clathrin adaptor protein (AP)-1B, which regulates the basolateral protein sorting, led to the massive reduction of IELs. Quantitative proteomics demonstrated that dozens of proteins, including known IEL-interacting proteins—E-cadherin, Btnl2, and Plexin B2—decreased in the basolateral membrane of AP-1B-deficient epithelial cells. Among the downregulated proteins, CD166 is included. CD166 interacted with CD6 on the surface of induced IELs. CD166 knockdown using shRNA in intestinal organoid culture significantly inhibited the recruitment of IELs to an epithelial layer. These data suggest that basolateral sorting by AP-1B is indispensable for maintaining IELs in the epithelial layer and survival of IELs.
2024-09-26 | PXD042900 | JPOST Repository
Project description:Relative expression levels of mRNAs in chicken IEL experimentally infected with EA, EM, or ET were measured at 1 to 6 days post-infection (dpi) following primary and secondary infections. One week-old chickens were uninfected (negative control) or were orally inoculated with sporulated oocysts of EA, EM, or ET. One week later, the infected chickens were challenged with an identical inoculum of the homologous parasite. Intestinal samples were collected daily from 5 birds in a treatment group at from 1 to 6 dpi following primary and secondary infections. Cecum, duodenum, and jejunum were collected from the birds challenged with E. acervulina, E. maxima, and E. tenella, respectively. Uninfected control samples and one of the 3 infection group samples were labeled with different fluorescent dyes and hybridized simultaneously on the same slide using a reference design with a dye swap protocol. Thirty seven-condition experiment, Non-infected control vs. Primary or secondary EA, EM, or ET infected IEL at 1 to 6. Biological replicates: 2 replicates with dye-switching from each infection groups. Two replicates per array.
2011-08-14 | E-GEOD-31213 | biostudies-arrayexpress