Novel role for the T-helper 17 signature cytokine IL-17: CD4 resistance to immune suppression
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ABSTRACT:
PROVIDER: PRJNA633631 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11809300.fastq.gz | Fastqsanger.gz | |||
| SRR11809301.fastq.gz | Fastqsanger.gz | |||
| SRR11809302.fastq.gz | Fastqsanger.gz | |||
| SRR11809303.fastq.gz | Fastqsanger.gz | |||
| SRR11809304.fastq.gz | Fastqsanger.gz |
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Project description:Important immune regulatory mechanisms mediated by CD4+ and CD8+ T-cells keep untoward CD4+ T-cell responses in check. CD4+ T-helper 17 (Th17) cells, characterized by IL-17 production, play critical roles in the body’s response to infections and cancer and in the pathogenesis of autoimmune diseases such as multiple sclerosis, psoriasis, arthritis, IBD, among others. Here we demonstrate that human CD4+ T-cells cells exposed to a Th17-differentiating milieu are highly resistant to immune suppression by CD8+ T-cells, compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T-cells themselves, but not through their action on CD8+ T-cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T-cells to induce suppressive resistance and this resistance can be reversed by blockade of IL-1, IL-6 or STAT3. These studies reveal a novel function for IL-17 cytokines in a CD4-intrinsic mechanism of immune resistance. The pathways induced in this process may serve as a critical target for intensive investigation and therapeutic intervention.
2020-08-26 | GSE150805 | GEO
Project description:Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1β, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.
| S-EPMC7430972 | biostudies-literature
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:Effect of cytokine treatment on mouse T helper cells
| PRJEB32838 | ENA
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:Interleukin-17 (IL-17)-secreting T helper 17 cells (Th17) are a recently identified CD4+ T helper subset that has been implicated in various inflammatory and autoimmune diseases. The issue of whether interleukin-17A (IL-17) contributes to hyperlipidemia-induced aortic endothelial cell activation remained unknown. Here, we reported that IL-17 contributes to hyperlipidemia-induced modulation of vascular cell gene expression during early atherosclerosis in vivo. Our results has shed lights onto the role of IL-17 on EC biology and has provided important insights for future development of novel therapeutics for early intervention of cardiovascular diseases and other inflammatory diseases.
2015-10-11 | GSE73907 | GEO
Project description:Skin contains poorly understood interdependent cellular networks that facilitate barrier integrity and host immunity, including neurons, and myeloid cells; the latter of which intrinsically express the pleiotropic cytokine IL-33. This work shows selective suppression of IL-33 expression in myeloid cells by activation of itch-sensing neurons bearing the Mas-related G protein receptor A3 (A3). Optogenetic activation of A3 neurons also increased IL-17-expressing γδ T cells, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni, partially through the neuropeptide CGRP. Cell-intrinsic loss of IL-33 in myeloid cells alters chromatin conformation, basally elevates expression and release of IL-17-inducing cytokines (e.g., IL-1β, IL-6), and expands macrophage and cDC2 differentiation, driving both tissue pathology (e.g., epidermal thickening, keratinocyte hyperplasia) and resistance to helminth infection. Our findings suggest a mechanism of cellular cross-talk allowing “itch” neuron activation to alter myeloid composition and cytokine expression patterns for reshaping skin architecture and driving immunity
2024-09-12 | GSE218833 | GEO
Project description:Skin contains poorly understood interdependent cellular networks that facilitate barrier integrity and host immunity, including neurons, and myeloid cells; the latter of which intrinsically express the pleiotropic cytokine IL-33. This work shows selective suppression of IL-33 expression in myeloid cells by activation of itch-sensing neurons bearing the Mas-related G protein receptor A3 (A3). Optogenetic activation of A3 neurons also increased IL-17-expressing γδ T cells, epidermal thickening, and resistance to the human pathogen Schistosoma mansoni, partially through the neuropeptide CGRP. Cell-intrinsic loss of IL-33 in myeloid cells alters chromatin conformation, basally elevates expression and release of IL-17-inducing cytokines (e.g., IL-1β, IL-6), and expands macrophage and cDC2 differentiation, driving both tissue pathology (e.g., epidermal thickening, keratinocyte hyperplasia) and resistance to helminth infection. Our findings suggest a mechanism of cellular cross-talk allowing “itch” neuron activation to alter myeloid composition and cytokine expression patterns for reshaping skin architecture and driving immunity
2024-09-12 | GSE218825 | GEO