IL-17 cytokines preferentially act on naïve CD4+ T cells
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ABSTRACT:
PROVIDER: PRJNA668790 | ENA |
REPOSITORIES: ENA
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Project description:CD4+ Th17 T cells are a key helper population in the regulation of both protective immunity during infection and in self-tolerance. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and thus a major therapeutic target for autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, both in murine and human systems. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4+ T-cells. Moreover, IL-17A, IL-17F and IL-17AF led to reduction in immune signaling genes, but an increase in interferon responsive genes across all treatments. In addition, IL-17A, IL-17F and IL-17AF treatment possessed differences in downstream transcriptional signaling, with IL-17AF heterodimer conferring both the greatest transcriptional change and suppressed phenotype. Detailed transcriptome analysis provides important functional insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling.
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2013-06-15 | E-GEOD-40413 | biostudies-arrayexpress
Project description:The IL-23/IL-17 immune axis is of central importance in psoriasis. However, the contribution of IL-17 family cytokines other than IL-17A to drive skin inflammation in psoriasis has not been fully established. To further elucidate the role of individual IL-17 family cytokines in psoriasis, we investigated their expression and localization in psoriasis skin at the mRNA and protein level. Moreover, we investigated the gene expression signatures induced by individual IL-17 family cytokines in human skin ex vivo as well as modulation of responses induced by the combination of IL-17 family cytokines in human keratinocytes by brodalumab, a human monoclonal antibody targeting the IL-17RA, versus the IL-17A blocking antibody ixekizumab. We demonstrate that IL-17A, IL-17AF, IL-17F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce inflammatory gene expression signatures in human skin ex vivo that correlate with those observed in psoriasis. Furthermore, we show that brodalumab, in contrast to ixekizumab, fully blocks gene expression responses induced by the combination of IL-17A, IL-17AF, IL-17F and IL-17C in human keratinocytes. These findings suggest that inhibition of several IL-17 family cytokines, e.g. by targeting of the IL-17RA receptor, could be a favored mechanism to obtain a profound suppression of the inflammatory processes in psoriasis and thereby achieve high levels of skin clearance and sustained efficacy in patients with psoriasis.
2021-04-07 | GSE158448 | GEO
Project description:CD4+ T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4+ T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies.
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Project description:Naïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.
2020-03-04 | PXD015315 | Pride
Project description:Multiple IL-17 family cytokines signaling through IL-17RA drive inflammatory pathways in psoriasis
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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