Small intestine intraepithelial CD4+ T cells after Toxoplasma gondii infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55067 | GEO | 2014/02/15
SECONDARY ACCESSION(S): PRJNA238368
REPOSITORIES: GEO
Similar Datasets
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. CD4+ T cells were cell sorted to analyze the differences resulting from the lack of Crtam expression during T. gondii infection.
2014-02-15 | E-GEOD-55067 | 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.
2024-07-28 | GSE272890 | GEO
Project description:Carbo2013 - Cytokine driven CD4+ T Cell differentiation and phenotype plasticity
CD4+ T cells can differentiate into different phenotypes
depending on the cytokine milieu. Here a computational and mathematical model with sixty ordinary differential equations representing a CD4+ T cell differentiating into either Th1, Th2, Th17 or iTreg cells, has been constructed.
The model includes cytokines,
nuclear receptors and transcription factors that define fate
and function of CD4+ T cells. Computational simulations
illustrate how a proinflammatory Th17 cell can undergo
reprogramming into an anti-inflammatory iTreg phenotype
following PPARc activation.
This model is described in the article:
Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity.
Carbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, Lu P, Philipson CW, Hoops S, Marathe M, Eubank S, Bisset K, Wendelsdorf K, Jarrah A, Mei Y, Bassaganya-Riera J
PLoS Computational Biology [2013, 9(4):e1003027]
Abstract:
Differentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARγ activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARγ. Deletion of PPARγ in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.
Author's comment:
CD4+ T cell computational model (Version 1.4)
Steady state corrected. There was a problem in the internalization of IL-17 in its mathematical function.
This model is hosted on BioModels Database
and identified
by: MODEL1304230001
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2024-09-02 | BIOMD0000000451 | BioModels
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:Spleens from the B6 mice were isolated and single cell suspension was made. CD4 T cells were purified from the splenocytes using magnetic bead separation. Briefly, Splenocytes were incubated with biotinylated antibody cocktail consisting of antibodies (Biolegend) to CD19, B220, CD11b, CD11c, NK1.1, Gr1, CD25 CD8. After a wash step, cells were incubated with streptavidin conjugated magnetic particles (BD Biosciences). After washing, CD4 T cells were isolated by applying a magnetic field and removing the untouched cells. Purified CD4 T cells were then activated with plate-bound anti-CD3 plus anti-CD28 in presence of either Th1 or Th17 or Th1/17 polarizing condition for 3 days. Total RNA from the 3 days differentiated Th1, Th17 and Th1/17 cells was isolated using mirVana miRNA isolation Kit (Invitrogen).
2017-09-13 | E-MTAB-5237 | biostudies-arrayexpress
Project description:Transforming growth factor-β (TGF-β) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-β in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-β signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF-β-receptor II (TGF-βRII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-βRII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-γ. Thus, TGF-β signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity. Experiment Overall Design: To better understand the basis for pathogenicity of TGF-βRII-deficient NK1.1+ T cells, we performed gene expression profiling of NK1.1+ and NK1.1â T cell subsets from Tgfbr2fl/fl x CD4-Cre mice. We limited our analysis to CD8+ T cell subsets because NK1.1+ CD8 T cells made up 70% of total NK1.1+ T cells in Tgfbr2fl/fl x CD4-Cre mice, and this T cell subset showed the greatest numerical increase compared to littermate control mice. Thus, in these experiments we used FACS-sorted NK1.1+ and NK1.1â CD8+ T cells from 15- to 17-day-old mutant mice and total CD8+ T cells from Tgfbr2fl/wt x CD4-Cre littermate controls. Experiment Overall Design: mRNA expression profiles of NK1.1+ and NK1.1â CD8+ T cells from Tgfbr2fl/fl x CD4-Cre (KO) mice were compared to NK1.1â T cells from littermate control Tgfbr2fl/WT x CD4-Cre (Control) mice.
2008-06-12 | E-GEOD-4178 | biostudies-arrayexpress
Project description:CD4+ and CD8+ T cells isolated from wild-type and Foxo1-deficient mice were analyzed by global gene expression profiling with Affymetrix array MOE 430 2.0. Results indicate Foxo1 regulates the expression of genes encoding positive regulators of T cell activation, differentiation, homeostasis, cell adhesion, cell migration, and cellular stress responses. CD4+ and CD8+ T cells were isolated for RNA extraction and hybridization on Affymetrix microarrays.
2009-02-28 | E-GEOD-15037 | biostudies-arrayexpress
Project description:Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be anti-inflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and anti-inflammatory Th1 cells is still elusive. Here we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild type Th1 cells. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection and blockage of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and anti-inflammatory Th1 cells.
2018-05-10 | GSE103173 | GEO
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.
2010-05-05 | E-GEOD-18085 | biostudies-arrayexpress
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