Small intestine intraepithelial CD4+ T cells after Toxoplasma gondii infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Marco Colonna
PROVIDER: E-GEOD-55067 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Retention of lymphocytes in the intestinal mucosa requires specialized chemokine receptors and adhesion molecules. Here we find that both CD4+CD8+ and CD4+T cells in the intestinal epithelium, as well as CD8+T cells in the intestinal mucosa and mesenteric lymph nodes, express the cell adhesion molecule Crtam upon activation, whereas the ligand of Crtam, Cadm1, is expressed on gut CD103+DCs. Lack of Crtam-Cadm1 interactions in Crtam-/- and Cadm1-/- mice results in loss of CD4+CD8+T cells, which arise from mucosal CD4+T cells that acquire a CD8 lineage expression profile. Following acute oral infection with T. gondii, both WT and Crtam-/- mice mounted a robust TH1 response, but markedly fewer TH17 cells were present in the intestinal mucosa of Crtam-/- mice. The almost exclusive TH1 response in Crtam-/- mice resulted in more efficient control of intestinal T. gondii infection.
2014-02-15 | GSE55067 | GEO
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2023-12-31 | E-MTAB-11982 | biostudies-arrayexpress
Project description:The intestinal mucosa harbors the largest accumulation of T lymphocytes in the body. While these T cells play an important role in immune homeostasis, they are also implicated in triggering and maintaining pathological intestinal inflammation. In humans they are poorly characterised, and even mouse transcriptomes have been reported for only a few individual cell types, many of which lack direct human equivalents. Using expression microarrays on T cells isolated from ileal biopsies and in silico analysis, we present here an unbiased, transcriptome-wide view of function in T cell subpopulations of the healthy human intestine and delineate signalling pathways that are distinct from those seen in peripheral blood T cells. Paired blood and intestinal biopsies from 6 age/sex matched healthy human subjects. Intestinal biopsies processed to release intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL). All samples then used to generate T effector memory (Tem) cells of CD4+ and CD8+ subsets by flow sorting. 6 individuals; 3 cell sources per individual (blood, LPL, IEL); 2 Tem subsets per cell source (CD4+ and CD8+). 36 arrays in total
2014-05-06 | E-GEOD-49877 | biostudies-arrayexpress
Project description:Background and aims: Cytotoxic T cells have long been postulated to facilitate autoimmune destruction of intestinal epithelium; and the precise causal events leading to inflammatory bowel diseases (IBDs) remain unresolved. CADM1, a membrane adhesion protein which can shed its extracellular ectodomain enters the systemic circulation as well as bind the receptor CRTAM present on CD8+ T cells. Methods: We performed RNA and small RNA sequencing on colon tissue from IBD and non-IBD (NIBD) control patients. We performed spatial transcriptomics and stimulated lamina propria mononuclear cells (LPMCs) with the soluble form of CADM (sCADM1) in these patients. Dextran Sulfate Sodium (DSS) was used to induced colitis in a conditional myeloid Cadm1 loss-of-function mouse. Results: MicroRNA-375 was significantly decreased while its direct target CADM1 was markedly up-regulated in UC patients compared to NIBD control subjects. Single cell proteomics data identified CADM1 enrichment in multiple clusters including macrophages and dendritic cells from colonic tissue of human subjects with IBD. An increased number of CADM1+CD68+ cells was detected adjacent to CD8+ T-cells within the intestinal epithelium of colon sections from patients with ulcerative colitis (UC) compared to NIBD subjects. Myeloid Cadm1 conditional knockout mice were protected against DSS-induced colitis indicating Cadm1 may facilitate binding/localization of cytotoxic cell populations within the gut epithelium. Furthermore, we observed that serum levels of the cleaved extracellular ectodomain of CADM1 (sCADM1) are elevated in medically refractory UC patients compared to non-IBD and UC donors in remission and treatment of LPMCs with recombinant sCADM1 enhanced STAT3 phosphorylation. Conclusions: Together these results identify CADM1 as a potent mediator of pro-inflammatory signaling pathways and demonstrate its potential as a diagnostic and therapeutic target for preventing the IBDs.
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Project description:The innate immune response of mucosal epithelial cells during pathogen invasion plays a central role in immune regulation in the gut. Toxoplasma gondii (T. gondii) is a protozoan intracellular parasite that is usually transmitted through oral infection. Although much of the information on immunity to T. gondii has come from intra-peritoneal infection models, more recent studies have revealed the importance of studying immunity following infection through the natural per-oral route. Oral infection studies have identified many of the key players in the intestinal response; however, they have relied on responses detected days to weeks following infection. Much less is known about how the gut epithelial layer senses and reacts during initial contact with the pathogen. Given the importance of epithelial cells during pathogen invasion, this study uses an in vitro approach to isolate the key players and examine the early response of intestinal epithelial cells during infection by T. gondii. We show that human intestinal epithelial cells infected with T. gondii elicit rapid MAPK phosphorylation, NF-κB nuclear translocation, and secretion of interleukin (IL)-8. Both ERK1/2 activation and IL-8 secretion responses were shown to be MyD88 dependent and TLR2 was identified to be involved in the recognition of the parasite regardless of the parasite genotype. Furthermore, we were able to identify additional T. gondii-regulated genes in the infected cells using a pathway-focused array. Together, our findings suggest that intestinal epithelial cells were able to recognize T. gondii during infection, and the outcome is important for modulating intestinal immune responses. Oral infection studies have demonstrated an increase in several cytokines and chemokines in response to T.gondii infection; however, the mixed population of the intestinal mucosa did not allow for the determination of the relative role that specific cell populations play in the production of these mediators. To address the role of intestinal epithelial cells to modulate the cytokine environment early following infection, we used specific pathway arrays to identify cytokines and chemokines induced 4 hours after exposure to T. gondii. At this time point most cells have become infected, but the parasites have not replicated.
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