The gene expression profile of CD4 T-cells with STAT3 gain-of-function and loss-of-function mutations
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ABSTRACT:
PROVIDER: PRJNA817580 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18371800_1.fastq.gz | Fastqsanger.gz | |||
| SRR18371800_2.fastq.gz | Fastqsanger.gz | |||
| SRR18371801_1.fastq.gz | Fastqsanger.gz | |||
| SRR18371801_2.fastq.gz | Fastqsanger.gz | |||
| SRR18371802_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions. Genome-wide transcription factors mapping and binding of STAT3 in mouse CD4+ T cells in both WT and Stat1-deficient mice. RNA-Seq is performed in mouse CD4+ T cells in WT, Stat1-deficient and Stat3-deficient mice.
2015-07-01 | E-GEOD-63204 | biostudies-arrayexpress
Project description:STAT3 Modulates CD4+ T Mitochondrial Dynamics and Function in Aging
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Project description:Interleukin-21 (IL-21) is a type 1 cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4+ T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4+ T cells. RNA-Seq analysis of CD4+ T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3, and interestingly, ChIP-Seq analysis showed that STAT3 binding at Tbx21 and Ifng loci was attenuated in Stat1-deficient cells. Moreover, opposing actions of STAT1 and STAT3 on IFN- expression in CD4+ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis (LCMV) infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4+ T cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES), which is caused by STAT3 deficiency. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.
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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.
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Project description:Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad spectrum of clinical features and prior studies have documented a decreased frequency of Foxp3+ regulatory T (Treg) cells and an increased frequency of Th17 cells is some patients. However, the precise mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from patients with STAT3 GOF syndrome. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these finding suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
2022-10-14 | GSE207934 | GEO
Project description:Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad spectrum of clinical features and prior studies have documented a decreased frequency of Foxp3+ regulatory T (Treg) cells and an increased frequency of Th17 cells is some patients. However, the precise mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from patients with STAT3 GOF syndrome. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these finding suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
2022-10-14 | GSE207935 | GEO
Project description:Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data shows that aging promotes an increase in localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and has a mechanistic link to T cell cytokine production. More specifically, mitoSTAT3 increased activity of aging T cell mitochondria due to STAT3’s effect on complex II. Limiting mitoSTAT3 using a mitochondria targeted curcuminoid, Mtcur-1, lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced proinflammatory Th17 inflammation. Exogenous expression of the constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and function in T cells from older adults and partially recapitulated aging-induced cytokine profiles. Our data shows the mechanistic link among mitoSTAT3, mitochondrial dynamics,function and T cell cytokine production.
2023-10-17 | GSE241492 | GEO
Project description:To investigate the effect of STAT1 gain of function on gene expression in CD4+ T cells, we sorted TCRβ+CD4+ CD44+ T cells from the spleens of STAT1 gain of function (STAT1 GOF/CMV Cre) and wild type C57BL/6J control mice of the same sexe by cell sorting.
2023-11-22 | GSE218608 | GEO
Project description: Not available
| S-EPMC5056811 | biostudies-literature