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Mus musculus strain:C57BL/6J

ABSTRACT: Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer

PROVIDER: PRJNA550456 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10748700_1.fastq.gz	Fastqsanger.gz
	SRR10748700_2.fastq.gz	Fastqsanger.gz
	SRR10748701_1.fastq.gz	Fastqsanger.gz
	SRR10748701_2.fastq.gz	Fastqsanger.gz
	SRR10748702_1.fastq.gz	Fastqsanger.gz

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Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer

Project description:Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer

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Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer

Project description:Background and aims: Gut microbial metabolites and their host signaling pathways hold therapeutic potential for colorectal cancer (CRC). One example is short-chain fatty acids (SCFA), which are microbial metabolites generated from dietary fiber. This study aims to determine the pathogenesis of CRC from the host-microbiota perspective and the contributions of Ffar2, a SCFA receptor, to CRC. Methods: We have employed Apc-based models of CRC in conjunction with Ffar2 knock-out (ko) mice, Ffar2 conditional ko mice, and Ffar2 chemical agonism to reveal how a microbial metabolite receptor influences tumorigenesis in the colon. Utilizing human CRC datasets from The Cancer Genome Atlas aided our discovery of the links between Ffar2 function in dendritic cells and tumoral T cell dysfunction. Herein, we also used preclinical CRC models to test IL-27p28 neutralization or Ffar2 agonism as proof of concept for CRC prevention and treatment. Results: We have identified a mechanism by which Ffar2 deficiency potentiates tumorigenesis by affecting gut barrier integrity that increases tumor bacterial load and then altering IL-27+ dendritic cell populations and tumor CD8+ T cell phenotype and function. These events create a tumor immune milieu notable for dying and over-activated DCs and exhausted CD8+ T cells, which enables tumor growth. Proof-of-concept experiments in mice employing IL-27p28 neutralization or Ffar2 agonism reduced tumor burden. Conclusions: Our data support that loss of Ffar2 signaling potentiates tumorigenesis via a “two-hit” model, first by gut barrier breach and then by immune cell dysfunction. Our work supports that altering Ffar2 signaling or neutralizing IL-27 represent potential immunotherapy CRC treatment strategies.

2020-01-16 | GSE142691 | GEO

CD4+ T cells license Kupffer cells to reverse the CD8+ T cell dysfunction induced by hepatocellular priming

Project description:CD4⁺ T cells are believed to be essential for effective CD8⁺ T cell responses against hepatotropic viruses like hepatitis B virus (HBV). However, the specific locations and the cellular and molecular mechanisms through which CD4⁺ T cells help CD8⁺ T cells remain unclear. In this study, we generated HBV-specific CD4⁺ TCR transgenic mice to demonstrate that effector CD4⁺ T cells can prevent or reverse the dysfunction of CD8⁺ T cells caused by hepatocellular priming. This, in turn, enhances CD8⁺ T cell effector function and suppresses viral replication. Notably, CD4⁺ T cell help to CD8+ T cells occurs directly in the liver, independent of secondary lymphoid organs, and requires local antigen recognition but not epitope linkage. While dendritic cells were found to be dispensable, Kupffer cells (KCs) emerged as the critical cellular platform for this effect. Mechanistically, CD4⁺ T cells engage KCs via CD40-CD40L interactions, leading to the production of IL-12 and IL-27. IL-12 promotes further CD4⁺ T cell expansion, whereas IL-27 serves as the key cytokine that restores CD8⁺ T cell functionality. Furthermore, we show that exogenous IL-27 administration can reverse HBV-specific CD8⁺ T cell dysfunction in mice and in chronically infected patients. These findings reveal a novel mechanism of CD4⁺ T cell help to CD8⁺ T cells that occurs outside secondary lymphoid organs, specifically in the liver, and involves antigen-presenting cells other than conventional dendritic cells, offering new insights for immunotherapeutic strategies against chronic HBV infection.

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Project description:Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

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Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

Project description:Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deletion of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived IL-22 production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings demonstrate that Ffar2 regulates colonic ILC3 proliferation and function in a cell-intrinsic manner and identifies an ILC3-receptor signaling pathway regulating gut inflammatory tone and pathogen defense.

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An interleukin-27 centered cytokine circuit regulates macrophage and T cell interactions in autoimmune diabetes

Project description:In the NOD mouse model of autoimmune diabetes, IL-27 stimulates CD4 and CD8 T cells to enhance their IFNγ production and diabetogenic capacity. Here, single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21+ Th1 phenotype. Consequently, IL-27 signaling in CD4 T cells was important for BATF and granzyme B expression in islet CD8 T effectors. Complete absence of IL-21 signaling in CD8 T cells additionally impaired their cytokine production. BATF overexpression increased the diabetogenic potential of β-cell autoreactive CD8 T cells lacking help from CD4 T cell-derived IL-21. Macrophages were the main source of IL-27 in islets, whose expression correlated with T cell infiltration. IFNγ and CD40 signaling conferred by activated T cells induced macrophage IL-27 production. Collectively, our findings reveal a role of IL-27 in orchestrating interconnected positive feedback loops involving CD4 T cells, CD8 T cells, and macrophages in autoimmune diabetes.

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Mus musculus breed:C57BL/6J

Project description:Dendritic cell response following Chlamydia trachomatis infection in Mus musculus

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