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Gene expression profile for naïve CD4+ T cells after 60-hour-treatment by IL-27

ABSTRACT: The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R-/- mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction. Through gene expression profile analysis, we identified a series of transcription factors that are induced by IL-27. Particularly, the induction of NFIL3 is highly relevant to Tim-3 expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE63628 | GEO | 2015/01/31

SECONDARY ACCESSION(S): PRJNA268498

REPOSITORIES: GEO

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Gene expression profile for naïve CD4+ T cells after 60-hour-treatment by IL-27

Project description:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R-/- mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction. Through gene expression profile analysis, we identified a series of transcription factors that are induced by IL-27. Particularly, the induction of NFIL3 is highly relevant to Tim-3 expression. Naïve CD4+ T cells from C57BL/6 mice were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies for 60 hours. The cells were subjected to gene profile analysis. A comparative transcriptome analysis between cells under neutral culture condition (Untreated) and cells treated with IL-27 (IL-27-treated) was peformed to screen transcription factors that are induced by IL-27 signaling.

2015-01-31 | E-GEOD-63628 | biostudies-arrayexpress

IL-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors

Project description:Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, while IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasitespecific effector T cells that expressed high levels of IR and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4 and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression, but find that during infection, IL-27 provides a signal that promotes T cell expression of inhibitory receptors.

2019-01-17 | GSE124222 | GEO

Interleukin-27 signaling serves as an immunological checkpoint for innate cytotoxic cells to promote hepatocellular carcinoma

Project description:While some of the inflammatory mechanisms driving hepatocellular carcinoma (HCC) had been proposed, the regulators of anti-cancer immunity in HCC remain poorly understood. We found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. High IL-27EBI3 or IL-27RA expression correlated with poor prognosis for patients with HCC. Loss of IL-27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL-27R signaling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL-27R ablation enhanced the accumulation and activation, while depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL-27R disruption. Pharmacological neutralization of IL-27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL-27R signaling as an immunological checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL-27 pathway blockade in HCC

2022-05-27 | GSE200040 | GEO

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

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.

2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders

Project description:High levels of inflammation are often present in autoimmune diseases and can impact the functioning of the immune system. Specifically, how surrounding inflammation affects cytokine responses has not been extensively studied. We use IL-6 and IL-27, two cytokines playing opposite roles in inflammation, to ask how cytokines adapt to the inflammatory environment. We show that IL-27 induces a more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identify STAT1 (or STAT3) binding dynamics to GP130 (or IL-27R) as the main parameter contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80%, with limited effect on STAT3 phosphorylation. The strong receptor/STAT coupling by IL-27 led to the induction of a unique gene expression program by this cytokine, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in Crohn’s disease and SLE patients. IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which can be explained by the higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib lowered the levels of STAT1 activation by IL-6, representing a new strategy to treat auto-immune disorders where cytokine responses are dysregulated.

2021-04-27 | GSE164479 | GEO

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

2015-11-01 | GSE63455 | GEO

Single cell RNAseq of Wild Type and IL27ra KO Tumor infiltrating lymphocytes isolated from B16F10 melanoma batch 1

Project description:Expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated co-inhibitory receptor expression on CD4+ T cells promotes autoimmunity while sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and cancer. Here, we used RNA and protein expression profiling at single-cell resolution to identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, Tim-3, Lag-3, and TIGIT), but also a number of novel surface receptors. We functionally validated two novel co-inhibitory receptors, Activated protein C receptor (Procr) and Podoplanin (Pdpn). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in multiple physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors Prdm1 and c-Maf as cooperative regulators of the co-inhibitory module, which we validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies novel regulators of T cell function with the potential to regulate autoimmunity and tumor immunity.

2018-06-14 | GSE113262 | GEO

RNAseq of Wild Type and Prdm1/c-Maf cDKO CD8+ Tumor infiltrating lymphocytes isolated from B16F10 melanoma

2018-06-14 | GSE113221 | GEO

RNAseq of Wild Type and IL27ra KO CD8+ Tumor infiltrating lymphocytes isolated from B16F10 melanoma.

2018-06-14 | GSE113208 | GEO

Microarray expression data of naïve CD4 and CD8 T cells stimulated with IL27.

2018-06-14 | GSE113216 | GEO