The impact of IL-33 on Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs
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PROVIDER: PRJNA1136871 | ENA |
REPOSITORIES: ENA
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Project description:Tregs are highly enriched in the eVAT of male mice. We show that ST2+ VAT Tregs preferentially upregulate and depend on Srebf2-mediated cholesterol metabolism compared their spleen Treg or ST2- VAT Treg counterparts. However, it is unclear whether this increased reliance on cholesterol metabolism is a consequence elevated IL-33 signaling in ST2+ Tregs. Therefore, the goal of experiment is to determine whether IL-33 signaling influences Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs in vivo.
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Project description:Foxp3+ regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis. Tregs that express the IL-33 receptor ST2 are enriched in peripheral nonlymphoid tissues and can exert a variety of tissue-specific functions from metabolic regulation within adipose tissue to skeletal muscle repair. However, the relationship between ST2+ and ST2- Tregs within and across different tissues remains unclear. To compare murine ST2- and ST2+ Tregs within and across tissues, we performed RNA sequencing (RNAseq) of ST2-CD44hi and ST2+CD44hi Tregs from blood, spleen, lungs, visceral adipose tissue (VAT), colon, and skin. RNAseq was also performed on ST2- CD44lo CD62L+ Tregs from the spleen and lungs. We found that the tissue microenvironment was the major factor shaping the transcriptome of Tregs across tissues. Across the tissues studied, Treg transcriptomes displayed an ordered hierarchy that may represent graded levels of activation or differentiation across tissues. We also identified a core signature that distinguished ST2+ Tregs from ST2- Tregs across tissues and a large number of differentially expressed genes between ST2- and ST2+ Tregs within individual tissues that could support the tissue-specific adaptation and function of ST2+ Tregs. In summary, our work highlights the unique, tissue-specific phenotype of ST2+ Tregs and reveals a core ST2+ Treg transcriptional signature shared across tissues.
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Project description:Because of the extensive data in mice supporting the concept that ST2+ Tregs might have desirable therapeutic properties, including tissue repair function, high suppressive capacity, and enhanced stability, we engineered human blood Tregs to constitutively express ST2 (IL-33R). Here we used RNA sequencing to explore the effects of short-term culture with IL-33 on human ST2-transduced Tregs.
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Project description:The effects of IL-33 on ST2+ Treg cells were not studied thouroughly. We FACS-sorted in vitro expanded ST2+ Treg cells from C57BL/6 Foxp3-IRES-mRFP (B6 FIR) mice. We next used RNA-seq techonology to define how recombinant IL-33 (rIL-33) may impact mouse Treg by to assessing the transcriptome of IL-33-stimulated ST2+ Treg cells compared to that of untreated ST2+ Treg cells. Our data revealed that ST2+ Treg stimulated with rIL-33 for 6 hours exhibited increased expression of Il10 and Il13 compared to unstimulated ST2+ Treg cells.
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Project description:Colorectal cancer (CRC) was induced in Foxp3/eGFP reporter mice by the azoxymethane/dextran sulphate sodium salt (AOM/DSS) protocol. Mice were injected i.p. with the procarcinogen AOM (12.5 mg/kg of body weight). After 1 week, mice received drinking water supplemented with 2.5% DSS for 5 to 7 days, followed by 2 weeks of regular water. The DSS administration was repeated twice with 2% DSS. Mice were sacrificed at week 11 and lamina propia lymphocytes (LPLs) from the colon were isolated. CD4+FOXP3+ (eGFP+) ST2+ or ST2- Tregs were separated from colonic LPLs of CRC induced mice using a FACSAria II cell sorter. Microarray analysis was performed to analyze if ST2+ FOXP3+ Tregs from the colon of CRC mice present a distinct transcription pattern compared to ST2- FOXP3+ Tregs. By this, the role of ST2 for Treg function during intestinal tumorigenesis should be characterized.
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