Interleukin-27 priming of T cells controls Interleukin-17-production in trans via induction of Programmed cell death ligand 1
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE38375 | GEO | 2012/07/01
SECONDARY ACCESSION(S): PRJNA167754
REPOSITORIES: GEO
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Project description:Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. The roles of IL-6 and IL-27 in naïve CD4+ T cells was investigated by comparing global gene expression by Affymetrix Mouse Genome 430 2.0 Arrays. The functional outcome of STAT proteins was further evaluated by profiling gene expression changes between WT and STAT-deficient T cells in naïve CD4+ T cells with specific stimulation. All condition were done in biological triplicate.
2012-06-30 | E-GEOD-38375 | biostudies-arrayexpress
Project description:T cells that encounter cultured ocular pigment epithelial cells in vitro are inhibited from undergoing T cell receptor-triggered activation. Because retinal pigment epithelial (RPE) cells are able to suppress T-cell activation, we studied whether RPE cells could suppress cytokine production by activated T helper (Th) cells. In this study we showed that primary cultured RPE cells greatly suppressed activation of bystander CD4+ T cells in vitro, especially the cytokine production by the target T helper cells (Th1 cells, Th2 cells, Th17 cells, but not Th3 cells). Cultured RPE cells and RPE-supernatants significantly suppressed IL-17 producing CD4+ T cells, and RPE cells fully suppressed polarized Th17 cell lines that induced by recombinant proteins, IL-6 and TGFb2. Moreover, RPE cells failed to suppress IL-17 producing T cells in the presence of rIL-6. In addition, Th17 cells exposed to RPE were suppressed via TGFb, which produce RPE cells. These results indicate that retinal PE cells have immunosuppressive capacity in order to inhibit Th17-type effector T cells. Thus, ocular resident cells play a role in establishing immune regulation in the eye. Retinal pigment epithelium suppresses Th17 cells
2012-07-11 | E-GEOD-22877 | biostudies-arrayexpress
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
Project description:IL-27, a member of the IL-12- family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune-regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-, induces the expression of IL-18BP, IDO and PD-L1 immune-regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN- display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27- regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels.
2017-05-19 | PXD004419 | Pride
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used. In order to capture complex gene expression changes in the PBMCs derived from 15 CIS patients in comparison to 7 HCs, we performed a comprehensive study using Affymetrix Human Gene array U133 (HG-U133) with 45,000 probe sets representing approximately 33,000 human genes. The arrays were hybridized for 16 h at 45oC in a GeneChip® Hybridization Oven 640 (Affymetrix), washed and stained with R-phycoerythrin streptavidin in a GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning, and basic analysis. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis of microarrays was used. Differentially expressed genes were determined using a Welch two sample t-test. A p<0.05 was considered significant.
2015-05-15 | E-GEOD-59085 | biostudies-arrayexpress
Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used.
2015-05-15 | GSE59085 | GEO
Project description:Targeting checkpoint blockade to rescue exhausted regulatory T cells (Tregs) has become an essential immunotherapy strategy in treating cancer. Until now, the CD4+ Tregs and PD-1+CD8+ T cells were demonstrated to reduce immunogenic responses. In contrast, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We performed two high-throughput analysis approaches on tumor-infiltrating CD8+ T cells in lung cancers. We discovered PD-L1+CD8+ T cells enriched in tumor lesions, localized with PD-1+CD8+ affected T cells, and owned regulatory functions. Moreover, tumor-derived IL-27 promoted the development of PD-L1+CD8+ T cells through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified the enrichment of PD-L1+CD8+ T cells related to the downregulation of adaptive immune response. Additionally, enrichment of this subset was correlated with poor survival of lung cancer patients. Our data collectively demonstrated that PD-L1+CD8+ T cells potentially become a prognostic biomarker in lung cancer.
2022-02-18 | GSE192591 | GEO
Project description:Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. Methods: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell-type specific deletion of IL-10- and IL-10Ra were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of IL-10 on PD-L1. Results: We found that Il10-deficient mice and mice treated with IL-10Ra antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e., monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. Conclusions: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer (CRC)-derived liver metastasis. These findings provide the basis for future monitoring and targeting of IL-10 in CRC-derived liver metastasis.
2024-02-09 | GSE247304 | GEO
Project description:In a syngeneic mouse model of melanoma, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, granulocytic myeloid-derived suppressor cells (GMDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated CD4+ and CD8+ T cells. Blocking IL-1 signaling decreased GMDSCs and their associated PD-L1 expression in the tumor microenvironment, and enhanced tumor-specific immunity.
2021-02-04 | GSE164357 | GEO