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Activation of gp130 signaling in T-cells drives TH17-mediated multi-organ autoimmunity

ABSTRACT: Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need. Methods: To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, in this study we constitutively activated the gp130/JAK/STAT3 axis by means of a transgene, L-gp130, specifically targeted to T-cells. Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. We observed strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production. Transcriptome profiling of murine CD4+ and CD8+ T-cells revealed commonly dysregulated genes and a STAT3 gain-of-function signature that was used to discriminate between STAT3 gain-of-function and healthy control patients. Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity

ORGANISM(S): Mus musculus

PROVIDER: GSE198849 | GEO | 2023/10/01

REPOSITORIES: GEO

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Activation of gp130 signaling in T-cells drives TH17-mediated multi-organ autoimmunity [WT vs Stat3c]

Project description:Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need. Methods: To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, in this study we constitutively activated the gp130/JAK/STAT3 axis by means of a transgene, L-gp130, specifically targeted to T-cells. Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. On a cellular level, strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production was observed. Transcriptome profiling of murine CD4+ and CD8+ T-cells of Lgp and Stat3C mice revealed commonly dysregulated genes and a gene signature that allowed for discrimination between STAT3 gain-of-function patients and healthy controls. In summary, we demonstrate that hyperactive gp130/STAT3 signaling leads to TH17-driven autoimmunity, phenotypically resembling human STAT3 gain-of-function disease. Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity

2022-12-01 | GSE199555 | GEO

The gene expression profile of CD4 T-cells with STAT3 gain-of-function and loss-of-function mutations

Project description:Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need. Methods: To decipher the crucial cellular subsets and disease biology associated with STAT3 gain-of-function mutations, we examined the gene expression profile of STAT3 gain-of-function and loss-of-function mutations in unstimulated, IL10- or IL21-stimulated CD4 T cells and compared them to healthy donor cells. Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. We observed strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production. Transcriptome profiling of murine CD4+ and CD8+ T-cells revealed commonly dysregulated genes and a STAT3 gain-of-function signature that was used to discriminate between STAT3 gain-of-function and healthy control patients. Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity

2023-10-06 | GSE198963 | GEO

A human STAT3 gain of function variant drives Th17 expansion and IL-22 dependent skin inflammation in a model of psoriasiform dermatitis

Project description:Germline gain-of-function (GOF) variants in STAT3 cause early-onset poly-autoimmunity and immune dysregulation. STAT3 is a pleiotropic transcription factor that affects the induction and regulation of immune responses, with diverse effects on the immune response. Using a mouse model of STAT3 GOF (p.G421R), we observed spontaneous and imiquimod (IMQ)-induced skin inflammation with increased cell-intrinsic local Th17 responses. CD4+ T cells were required and sufficient to drive skin inflammation, and upregulated Il22 expression in expanded clones. However, certain aspects of disease, including epidermal thickness, required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease, without affecting local Th17 recruitment and cytokine production. Collectively, these data support a role for a Th17 response and in the development of organ-specific immune dysregulation in STAT3 GOF, and also suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.

2024-04-09 | GSE240205 | GEO

Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

2008-12-24 | GSE11819 | GEO

Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours

Project description:Inflammatory hepatocellular adenomas (IHCA) are benign liver tumours defined by the presence of inflammatory infiltrates and by the elevated expression of inflammatory proteins in tumour hepatocytes1,2. Here we show a striking activation of the IL6 signalling pathway in this tumour type, and sequencing candidate genes pinpointed this response to somatic gain-of-function mutations in the IL6ST gene that encodes the signalling co-receptor gp130. Indeed, ~70% of IHCA harbour small in-frame deletions that target the binding site of gp130 for IL6, and expression of the most frequent gp130 mutant, Delta-STVY190, in hepatocellular cells activates STAT3 in absence of ligand. Further, analysis of hepatocellular carcinomas revealed rare gp130 alterations always accompanied by M-CM-^_-catenin-activating mutations, suggesting a cooperative effect of these signalling pathways in the malignant conversion of hepatocytes. The recurrent gain-of-function gp130 mutations in these human hepatocellular adenomas explains their inflammatory phenotype, and suggest that similar alterations may occur in other inflammatory epithelial tumours with STAT3 activation. HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 4 Inflammatory hepatocellular adenomas (IHCA) and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions (Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 8 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, 282(19):14437-46, PMID: 17379603; Rebuissou et al., J Hepatol 2008, 49(1):61-71. PMID: 18466996 and Rebuissou et al., in preparation].

2008-12-24 | E-GEOD-11819 | biostudies-arrayexpress

Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis

Project description:STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4+ T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4+ T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis. This SuperSeries is composed of the following subset Series: GSE21669: Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [ChIP-seq] GSE21670: Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [Affymetrix Expression] Refer to individual Series

2010-05-29 | E-GEOD-21671 | biostudies-arrayexpress

Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [Affymetrix Expression]

Project description:STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4+ T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4+ T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis. WT and STAT3-deficient CD4+ T cells were activated with anti-CD3 and anti-CD28, in the presence of cytokines (interleukin (IL)-6 and TGFb) or medium alone for three days. RNA was extracted and hybridized to Affymetrix microarray chips.

2010-06-08 | E-GEOD-21670 | biostudies-arrayexpress

CIP2A negatively regulates Th17 differentiation

Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.

2020-05-26 | PXD010612 | Pride

Genome-wide binding of STAT3 and STAT5 under Th17 conditions (ChIP-Seq)

Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The genome-wide binding of STAT3 and STAT5 under Th17 conditions was investigated by CHIP-seq.

2011-02-09 | E-GEOD-26552 | biostudies-arrayexpress

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

Project description:Cytokines activate signaling via assembly of cell surface receptors, but it is unclear whether modulation of cytokine-receptor binding parameters can modify biological outcomes. We have engineered IL-6 variants with different affinities to gp130 to investigate how cytokine receptor binding dwell-times influence functional selectivity. Engineered IL-6 variants showed a range of signaling amplitudes and induced biased signaling, with changes in receptor binding dwell-times affecting more profoundly STAT1 than STAT3 phosphorylation. We show that this differential signaling arises from defective translocation of ligand-gp130 complexes to the endosomal compartment and competitive STAT1/STAT3 binding to phospho-tyrosines in gp130, and results in unique patterns of STAT3 binding to chromatin. This leads to a graded gene expression response and differences in ex vivo differentiation of Th17, Th1 and Treg cells. These results provide a molecular understanding of signaling biased by cytokine receptors, and demonstrate that manipulation of signaling thresholds is a useful strategy to decouple cytokine functional pleiotropy.

2019-12-03 | GSE130810 | GEO

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