T helper cells modulate intestinal stem cell renewal and differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106510 | GEO | 2018/11/01
REPOSITORIES: GEO
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Project description:In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.
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Project description:T helper cells modulate intestinal stem cell renewal and differentiation
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Project description:Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced diversity of the intestinal microbiome and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor (PRR) and IFN g signaling regulate epithelial MHC-II expression where genetic ablation of these signaling pathways dampen MHC-II epithelial expression. Interestingly, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts when transplanted into immune-component hosts but not immune-deficient hosts, thus implicating a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD perturbs a microbiome – stem cell – immune cell crosstalk in the intestine and contributes to tumor initiation through the dampening of MHC-II expression in pre-malignant ISCs.
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Project description:Elf5 is a transcription factor with pivotal roles in the trophoblast compartment where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the current study we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome and genome-wide chromatin immunoprecipitation data we reveal that this abundance-dependent function is mediated through a shift in preferred Elf5 binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes driving their expression. By contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double and single occupancy sites that harbour the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the centre of a stoichiometry-sensitive transcriptional network where it acts as molecular switch governing the balance between TSC proliferation and differentiation.
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Project description:Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFKB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.
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Project description:Associative learning refers to our ability to learn about regularities in our environment. When a stimulus is repeatedly followed by a specific outcome, we learn to expect the outcome in the presence of the stimulus. We are also able to modify established expectations in the face of disconfirming information (the stimulus is no longer followed by the outcome). Both the change of environmental regularities and the related processes of adaptation are referred to as extinction. However, extinction does not erase the initially acquired expectations. For instance, following successful extinction, the initially learned expectations can recover when there is a context change - a phenomenon called the renewal effect, which is considered as a model for relapse after exposure therapy. Renewal was found to be modulated by reminder cues of acquisition and extinction. However, the mechanisms underlying the effectiveness of reminder cues are not well understood. The aim of the present study was to investigate the impact of reminder cues on renewal in the field of human predictive learning. Experiment I demonstrated that renewal in human predictive learning is modulated by cues related to acquisition or extinction. Initially, participants received pairings of a stimulus and an outcome in one context. These stimulus-outcome pairings were preceded by presentations of a reminder cue (acquisition cue). Then, participants received extinction in a different context in which presentations of the stimulus were no longer followed by the outcome. These extinction trials were preceded by a second reminder cue (extinction cue). During a final phase conducted in a third context, participants showed stronger expectations of the outcome in the presence of the stimulus when testing was accompanied by the acquisition cue compared to the extinction cue. Experiment II tested an explanation of the reminder cue effect in terms of simple cue-outcome associations. Therefore, acquisition and extinction cues were equated for their associative histories in Experiment II, which should abolish their impact on renewal if based on simple cue-outcome associations. In contrast to this prediction, Experiment II replicated the findings from Experiment I indicating that the effectiveness of reminder cues did not require direct reminder cue-outcome associations.
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Project description:During the chronic stage of Schistosoma infection, the female lays fertile eggs, triggering a strong anti-parasitic Type 2 helper T cell (Th2) immune response. It is unclear how this Th2 response gradually declines even though the worms live for years and continue to produce eggs. Here, we show that S. mansoni downregulates Th2 differentiation in an antigen presenting cell-independent manner, by modulating the Th2-specific transcriptional program. Adult schistosomes secrete miRNA-harboring extracellular vesicles that are internalized by Th cells in-vitro. Schistosomal-miRNAs are found also in T helper cells isolated from Peyer's patches and mesenteric lymph nodes of infected mice. In T helper cells, the schistosomal miR-10 targets MAP3K7 and consequently down-modulates NF-kB activity, a critical transcription factor for Th2 differentiation and function. Our results explain, at least partially, how schistosomes tune down the Th2 response, and provide further insight into the reciprocal geographical distribution between high prevalence of parasitic infections and immune disorders such as allergy. Furthermore, this worm-host crosstalk mechanism can be harnessed to develop diagnostic and therapeutic approaches for human schistosomiasis and Th2-associated diseases.
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Project description:During the chronic stage of Schistosoma infection, the female lays fertile eggs, triggering a strong anti-parasitic type 2 helper T-cell (Th2) immune response. It is unclear how this Th2 response gradually declines even though the worms live for years and continue to produce eggs. Here, we show that Schistosoma mansoni downregulates Th2 differentiation in an antigen-presenting cell-independent manner, by modulating the Th2-specific transcriptional program. Adult schistosomes secrete miRNA-harboring extracellular vesicles that are internalized by Th cells in vitro. Schistosomal miRNAs are found also in T helper cells isolated from Peyer's patches and mesenteric lymph nodes of infected mice. In T helper cells, the schistosomal miR-10 targets MAP3K7 and consequently downmodulates NF-?B activity, a critical transcription factor for Th2 differentiation and function. Our results explain, at least partially, how schistosomes tune down the Th2 response, and provide further insight into the reciprocal geographic distribution between high prevalence of parasitic infections and immune disorders such as allergy. Furthermore, this worm-host crosstalk mechanism can be harnessed to develop diagnostic and therapeutic approaches for human schistosomiasis and Th2-associated diseases.
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