Interleukin-17 directly stimulates tumor infiltrating Tregs to prevent cancer development [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE262405 | GEO | 2024/06/14
REPOSITORIES: GEO
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Project description:Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses. Here we show in mice that IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors, as well as in patients with colorectal cancer (CRC). Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function. Taken together, we report a direct role of IL-17 in promoting Treg maturation and function in CRC.
2024-06-14 | GSE262402 | GEO
Project description:Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of these cytokines is effective for treating psoriasis, IL-12/23 inhibition attenuates Crohn's disease, while IL-17A or IL-17RA inhibition exacerbates disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the mdr1a- /- mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing Treg accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provides insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.
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Project description:The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal carcinogenesis (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3YFP-Cre), and mice harboring a Treg cell-specific deletion of IL-23 (Il23rΔTreg). Il23rΔTreg mice had increased dysplasia compared to WT mice associated with decreased tumor-infiltrating macrophages. The role of Treg cell IL-23R in sporadic CRC was examined via orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. In the sporadic cancer model, Il23rΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23rΔTreg mice had a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4+ T cells. This data suggests that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4+ T cells that in turn promotes pro-inflammatory macrophages to clear tumors. These findings further support and highlight the importance of selecting a physiologically relevant model based on the type of cancer in which to evaluate the role of specific genes in late tumorigenesis. Finally, single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
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Project description:Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. However, the role of epithelial cell-derived cytokines in regulation of Treg cells in colorectal cancers is not fully understood. We found a subset of Tregs co-expressing the receptors for thymic stromal lymphopoietin (TSLP) and IL-33 (TSLPR+ST2+ Tregs) was increased in colorectal tumors in humans and mice. This Treg subset expressed high levels of CTLA-4 and PD-1, and TSLPR signaling regulated the expression of CTLA-4 and number of TSLPR+ST2+ Tregs. Treg-specfic deletion of TSLPR resulted in a reduction in tumor number and size, with concomitant increase of Th1 cells in tumors. Similarly, blockade of TSLP effectively inhibited progression of colorectal tumors. On the other hand, TSLPR-ST2+ Tregs highly express Tgfb1 and Pdcd,1 which have been shown to suppress CD8+ T cell immune responses. Collectively, TSLP and IL-33 differentially regulate subsets of Tregs in the progression of colorectal tumor. These data suggest that TSLPR+ST2+ Treg cells are potentially a biomarker, and a therapeutic target for CRC.
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Project description:IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution for IL-2 during Treg thymic development, peripheral homeostasis, and lineage stability remains unclear. Here we show that IL-2R signaling is essential for thymic Tregs at an early step for expansion/survival and a later step for functional maturation. Using selective deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling was absolutely essential for their persistence whereas Treg lineage stability was IL-2-independent. CD25 knockout peripheral Tregs showed increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2 transcriptional signature was noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, where peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.
2019-02-01 | GSE121883 | GEO
Project description:IL-17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. The cellular compartment and downstream molecular mediators of IL-17-mediated pancreatic tumorigenesis have not been fully identified. We interrogated the cellular compartment required by generating transgenic animals with Interleukin 17 receptor A (IL-17RA) genetically deleted from the pancreatic epithelial compartment vs. the hematopoietic compartment via generation of IL-17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL-17RA from the pancreatic epithelial compartment, but not from hematopoietic, resulted in delayed premalignant lesions initiation and progression and increased CD8+ cytotoxic T cells infiltration to the tumor microenvironment. Absence of IL-17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness and immunological pathways. Interestingly, B7-H4, a known inhibitor of T cell activation encoded by the gene Vtcn1, was the most upregulated checkpoint molecule via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed pancreatic premalignant lesions development and reduced immunosuppression. We reveal pancreatic epithelial IL-17RA requirement for pancreatic tumorigenesis by reprogramming the immune pancreatic landscape which is partially orchestrated by regulation of B7-H4.
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Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.
2015-05-19 | E-GEOD-68991 | biostudies-arrayexpress
Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.
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Project description:Regulatory T cells (Tregs) are enriched in the tumor microenvironment (TME) and suppress anti-tumor immunity. However, the origin of tumor-infiltrating (TI) Tregs and the molecular mechanism underlying their TME accumulation are poorly understood. Although IL-33 was reported to regulate the expansion and function of Tregs, its direct role on TI Tregs and its contribution to tumor progression remain uncertain. Firstly, we demonstrated TI Tregs were primarily thymus-derived. More importantly, we found using comparative transcriptome analysis that proliferation-related genes were prominently upregulated in TI Tregs compared with TI CD4+Foxp3− conventional T cells or splenic Tregs of same tumor-bearing mice. One of these genes, ST2, an interleukin-33 (IL-33) receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL-33-directed ST2 signaling induced the preferential proliferation of TI Tregs and enhanced tumor progression, while genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrate the IL-33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of thymus-derived Tregs in the TME and suggest the axis as a potential therapeutic target for cancer immunotherapy.
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Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.
2015-05-19 | GSE68991 | GEO