Ahr-Foxp3-RORγt Axis Controls Gut Homing of CD4+ T Cells by Regulating GPR15
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ABSTRACT:
PROVIDER: PRJNA564732 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10092114.fastq.gz | Fastqsanger.gz | |||
| SRR10092115.fastq.gz | Fastqsanger.gz | |||
| SRR10092116.fastq.gz | Fastqsanger.gz | |||
| SRR10092117.fastq.gz | Fastqsanger.gz | |||
| SRR10092118.fastq.gz | Fastqsanger.gz |
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Project description:The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression both in mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut Tregs in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role at least in part by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating Treg intestinal homing under the steady state and during inflammation, and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes.
2020-07-29 | GSE137171 | GEO
Project description:The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here, we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression in both mice and human, thus gut homing of T lymphocytes. Mechanistically, Ahr directly binds to open chromatin regions of the Gpr15 locus to enhance its expression. Ahr transcriptional activity in directing GPR15 expression was modulated by two transcription factors, Foxp3 and RORγt, both of which are expressed preferentially by gut regulatory T cells (Tregs) in vivo. Specifically, Foxp3 interacted with Ahr and enhanced Ahr DNA binding at the Gpr15 locus, thereby promoting GPR15 expression. In contrast, RORγt plays an inhibitory role, at least in part, by competing with Ahr binding to the Gpr15 locus. Our findings thus demonstrate a key role for Ahr in regulating Treg intestinal homing under the steady state and during inflammation and the importance of Ahr-RORγt-Foxp3 axis in regulating gut homing receptor GPR15 expression by lymphocytes.
| S-EPMC7371246 | biostudies-literature
Project description:GPR15+ vs GPR15- tumor-associated Tregs were sorted from colorectal cancer mice (Foxp3-RFP x GPR15-GFP)
2021-03-12 | GSE168744 | GEO
Project description:Foxp3-expressing regulatory (Treg) T cells are essential for immunological tolerance, where loss of this transcription factor leads to uncontrolled T cell responses and their associated clinical presentation of systemic autoimmunity in mice and humans. Importantly, Foxp3+ Tregs result from different origins and are either generated in the thymus (tTreg) or from conventional CD4+ T cells in the periphery (pTreg). In addition, Treg cells may adopt specific effector Treg phenotypes, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3+ T cells expressing the Th17 master transcription factor, RORγt, represent a stable effector Treg lineage that is specifically enriched in intestinal organs and gut-associated lymphoid tissues in mice possessing a complex microbial microflora. Simultaneous expression of Foxp3 and RORγt promotes the transcription of both Treg- and Th17-associated genes in Foxp3+RORγt+ T cells; however, epigenetic profiling of the Treg-specific demethylated region (TSDR) and other Treg-associated genes revealed a high degree of similarity between conventional Tregs and Foxp3+RORγt+ T cells, indicating that these cells have a stable regulatory, rather than inflammatory, function. Indeed, adoptive transfer of Foxp3+RORγt+ T cells in the context of T cell transfer colitis not only confirmed their Treg function and lineage stability in vivo, it also revealed a significantly enhanced regulatory capacity as compared to RORγt+ Treg cells. Thus, our data suggest that RORγt expression in Tregs is essential for optimal regulation of gut-specific immune responses, which renders them an important effector Treg lineage in the intestinal system.
2014-12-31 | GSE60059 | GEO
Project description:T helper 17 and Regulatory T cells (Th17 and Treg, respectively) are two well-described lymphocyte subsets with opposing actions. The divergent fates of Th17 and Treg cells are accounted for, at least in part, by molecular antagonism that occurs between their respective specific transcription factors, RORγt and Foxp3. An imbalance between Th17 and Treg cells may lead to tissue inflammation and is associated with certain types of autoimmunity. In order to understand the heterogeneity and dynamics of the differentiation process, we studied Th17/Treg cell differentiation of naïve cells in vitro, using RORγtGFPFoxp3RFP dual-reporter mouse. Flow cytometry revealed the consistent emergence of a population of double positive RORγt+Foxp3+ (DP) cells during the early stages of Th17 cell differentiation. These DP cells are closely related to RORγt+ single positive (SPR) cells in terms of global gene expression. Nevertheless, for some genes, DP cells share an expression pattern with Foxp3+ single positive (SPF) Treg cells, most importantly by reducing IL17 levels. Using time-lapse microscopy, we could delineate the expression dynamics of RORγt and Foxp3 at a clonal level. While the RORγt expression level elevates early during differentiation, Foxp3 rises later and is more stable upon environmental changes. These distinct expression profiles are independent of each other. During differentiation and proliferation, individual cells transit between SPR, DP, and SPF states. Nevertheless, the differentiation of sister cells within a clone progeny was highly correlated. We further demonstrated that sorted SPR and DP populations were not significantly affected by changes in their environment, suggesting that the correlated fate decision emerged at early time points, before the first division. Overall, this study provides the first quantitative analysis of differentiation dynamics during the generation of DP RORγt+Foxp3+ cells. Characterizing these dynamics and the differentiation trajectory could provide a profound understanding and be used to better define the distinct fates of T cells, critical mediators of the immune response.
2023-09-10 | GSE227988 | GEO
Project description:GPR15 is an orphan G-protein coupled receptor and its expression is abundant among T cells in the large intestine lamina propria. We used microarrays to examine charateristics of GPR15- vs GPR15+ CD4+ T cells in LILP and identified distinct classes of up-regulated genes in GPR15+ CD4+ T cells. We have generated GFP knock-in mice in GPR15 locus and used GFP as a maker for GPR15 expression. In heterozygous mice, GPR15+CD4+ T cells and GPR15-CD4-T cells were sorted and RNA was prepared from them.
2013-05-09 | E-GEOD-45773 | biostudies-arrayexpress
Project description:Th17 cells are potent mediators in autoimmune diseases and RORγt is required for their development. Recent studies have shown that RORγt+ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt+ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt+ Treg in their transcriptomes, peripheral RORγt+ Treg cells were derived from Foxp3+ thymic Treg cells, in an antigen-specific manner. Development of these RORγt+ Treg cells, coined as T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17 cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates Tr17 cells as effector Treg cells that potentially restrict autoimmunity.
2017-08-31 | GSE103319 | GEO
Project description:GPR15+ vs GPR15- tumor-associated Tregs
| PRJNA713801 | ENA
Project description:GPR15 is an orphan G-protein coupled receptor and its expression is abundant among T cells in the large intestine lamina propria. We used microarrays to examine charateristics of GPR15- vs GPR15+ CD4+ T cells in LILP and identified distinct classes of up-regulated genes in GPR15+ CD4+ T cells.
2013-05-09 | GSE45773 | GEO
Project description:Viral myocarditis is characterised by infiltration of mononuclear cells essential for virus elimination. GPR15 has been identified as a homing receptor for regulatory T cells in inflammatory intestine diseases, but its role in inflammatory heart diseases is still elusive. Therefore, we investigated the role of GPR15 during coxsackievirus B3‑induced myocarditis utilizing GPR15‑deficient mice as well as using in vitro experiments. Here we show that GPR15 deficiency had no effect on susceptibility to virus infection, but virus elimination was scant leading to adverse cardiac remodelling and impaired cardiac function. Delayed recruitment of regulatory T cells was accompanied by prolonged persistence of cytotoxic T cells as well as regulatory T cells in GPR15-deficient mice. Further, RNA sequencing revealed prolonged inflammatory response and altered chemotaxis in GPR15-deficient mice. In line, we identified GPR15 and its ligand GPR15L as an important chemokine receptor-ligand pair for the recruitment of regulatory and cytotoxic T cells. In summary, the insufficient virus elimination might be caused by a delayed recruitment of T cells as well as delayed interferon-γ expression, resulting in a prolonged inflammatory response and an adverse outcome in GPR15-deficient mice.
2023-11-24 | GSE248521 | GEO