Neonatal T helper 17 responses are skewed towards an immunoregulatory interleukin-22 phenotype
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135467 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:Newborns are frequently affected by mucocutaneous candidiasis. Th17 cells essentially limit mucosal invasion by commensal Candida spp. Here, we sought to understand the molecular basis for the developmental lack of Th17 cell responses in circulating blood neonatal T cells. Naive cord blood CD4 T cells stimulated in Th17-differentiating conditions inherently produced high levels of the interleukin-22 immunoregulatory cytokine, particularly in the presence of neonatal antigen-presenting cells. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells ex vivo revealed major developmental differences in gene networks regulating Small Drosophila Mothers Against Decapentaplegic (SMAD) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. These changes were functionally validated by experiments showing that the requirement for TGF-β in human Th17 cell differentiation is age-dependent. Moreover, STAT3 activity was profoundly diminished while overexpression of the STAT3 gene restored Th17 cell differentiation capacity in neonatal T cells. These data reveal that Th17 cell responses are developmentally regulated at the gene expression level in human neonates. These developmental changes may protect newborns against pathological Th17 cell responses, at the same time increasing their susceptibility to mucocutaneous candidiasis.
| S-EPMC8126652 | biostudies-literature
Project description:Neonatal T helper 17 responses are skewed towards an immunoregulatory interleukin-22 phenotype
| PRJNA558982 | ENA
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: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.
2012-07-12 | GSE22877 | GEO
Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program. Genome-wide binding analysis of Blimp1 from in vitro generated T effector and regulatory cells
2016-06-15 | E-GEOD-75724 | biostudies-arrayexpress
Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.
2016-06-15 | GSE75724 | GEO
Project description:Multiple sclerosis is a chronic autoimmune disease driven by pathogenic Th17 cells. Here, we dissected the role of miR-22 in pathogenic Th17 cells by autoantigen-specific disease models. We first showed that miR-22 was upregulated in peripheral lymphoid organs and spinal cords of mice developed autoimmune encephalomyelitis. Although miR-22 was upregulated in multiple helper T cell subsets, it was dispensable for T helper cell differentiation in vitro. While miR-22-/- mice exhibited milder symptoms of disease in an active EAE model, adoptive transfer of miR-22-/- 2D2 Th17 cells into naive recipient mice promoted higher disease incidence and severity compared to mice transferred with control 2D2 Th17 cells. Global transcriptional analysis of miR-22-deficient pathogenic Th17 cells revealed upregulated genes in phosphatase and tensin homologue (PTEN)-mediated pathways, and Pten was further identified as one of its potential targets. Therefore, we identified that Th17 cell intrinsic-miR-22 could protect mice from autoimmunity by targeting PTEN-regulated pathways.
2020-05-22 | GSE134895 | GEO
Project description:Using mass spectrometry-based label free quantitative proteomics analysis of in vitro differentiated murine Th17 and induced T regulatory (iTreg) cells. More than 4000 proteins covering almost all subcellular compartments were detected. Quantitative comparison of the protein expression profiles resulted in the identification of proteins specifically expressed in the Th17 and iTreg cells. Importantly, our combined analysis of proteome and gene expression data revealed protein expression changes that were not associated with changes at the transcriptional level.
2018-06-05 | PXD007826 | Pride
Project description:Since their recent discovery, T helper 17 (Th17) cells have been frequently detected in the tumor microenvironment of many malignancies, but their clinical implications remain largely unknown. Interleukin-17 (IL-17) detection is commonly related with poor outcomes in colorectal cancers, yet its presence is associated with antitumor responses in ovarian carcinomas. Numerous experimental models illustrate the divergent roles of Th17 cells in tumor immunity, which appears to be mainly dependent on the tumor context (type, location, and stage of cancer). It is recognized that IL-17 is produced by a variety of cell types and that Th17 cells are endowed with a unique functional plasticity. Therefore, when trying to elucidate potential immune biomarkers and immunotargets, it is extremely important to make a clear dissociation between strategies targeting Th17 versus its hallmark cytokine, IL-17. In this review, we will summarize the data regarding the detection of IL-17 and Th17 in human cancers, consider the experimental evidence on their respective roles in antitumor activity, and discuss the potential of IL-17 as an immune target for therapeutic interventions.
| S-EPMC4918233 | biostudies-literature
Project description:T helper (Th) 17 cells form a T cell subset which is crucial to maintain immunity against extracellular bacteria and fungi at epithelial barriers, but Th17 cells are also enriched at sites of inflammation in autoimmune disease. These sites are commonly characterised by adverse environmental conditions which are prone to trigger an ER (endoplasmic reticulum)-stress response. Our lab recently observed that the ER-stress response can be a strong driving force for Th17 cell differentiation. The aim of this RNA-seq project was to characterise the novel Th17 cell population generated by IL-6 and cyclopiazonic acid (CPA)-induced ER stress by transcriptional profiling of ER-stress generated and conventional Th17 cells. For this purpose nave IL17A-Cre Rosa-RFP CD4 T cells were cultured with a combination of Interleukin 6 with Transforming growth factor (TGF) or CPA for three days. Then, RFP-positive Th17 cells from four different experiments were enriched for by FACS sorting. Following RNA isolation using QIAGEN's RNA Mini Plus Kit and rRNA depletion accomplished with the NEBNext rRNA Depletion Kit, RNA-seq libraries were generated using the undirectional NEBNext Ultra RNA Library Prep Kit for Illumina. The libraries were sequenced as 75bp paired-end reads on a NextSeq 500 sequencer and analysed using QIAGEN's Biomedical Workbench.
2017-06-14 | E-MTAB-5692 | biostudies-arrayexpress