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A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [bulk RNA-seq]

ABSTRACT: A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [bulk RNA-seq]

PROVIDER: PRJNA857718 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20089539_1.fastq.gz	Fastqsanger.gz
	SRR20089539_2.fastq.gz	Fastqsanger.gz
	SRR20089540_1.fastq.gz	Fastqsanger.gz
	SRR20089540_2.fastq.gz	Fastqsanger.gz
	SRR20089541_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

Project description:A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

| PRJNA857714 | ENA

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [bulk RNA-seq]

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

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [single cell RNA-seq]

2022-10-14 | GSE207935 | GEO

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [single cell RNA-seq]

Project description:A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice [single cell RNA-seq]

| PRJNA857717 | ENA

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice.

Project description:Primary immune regulatory disorders (PIRD) represent 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 clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. 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 numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

| S-EPMC9675480 | biostudies-literature

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-14 | GSE207936 | 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

Genome Wide Binding profile and transcriptome of STAT3 and STAT3 Mutant Y640F in STAT3 Wildtype and STAT3 Mutant Y640F hematopoietic progenitor cell lines

Project description:In many human cancers the transcription factor STAT3 is constitutively active and contributes to oncogenesis, tumour growth and progression. Recently, gain-of-function mutations of STAT3 have been identified in patients suffering from various haematopoietic malignancies and are postulated to enhance the transcriptional activity of STAT3. We investigated the gene expression and binding profile of the most common STAT3 mutant Y640F compared to wild-type STAT3, describing it's mechanism of action and pinpointing to novel therapeutic intervention sites.

2023-01-25 | GSE211111 | 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

Treg specific Gata3 knock out array

Project description:The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (Treg cells). To gain insights into the molecular mechanisms of Foxp3 mediated gene expression we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multi-protein complexes of 400-800 kDa or larger and identified 361 associated proteins ~30% of which are transcription-related. Foxp3 directly regulates expression of a large proportion of the genes encoding its co-factors. Reciprocally, some transcription factor partners of Foxp3 facilitate its expression. Functional analysis of Foxp3 cooperation with one such partner, Gata3, provided further evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of Treg cell biology. Gene expression profile of Treg specific knock-out of Gata3 vs. their littermate controls were analyzed to gain insight into Gata3 dependendent genes in Treg cells. Treg cells (CD4+CD25+YFP+) sorted from Gata3F/FFoxp3YFP-Cre and Gata3F/+Foxp3YFP-Cre mice (three mice in each group) followed by microarray analyses.

2012-08-28 | E-GEOD-39864 | biostudies-arrayexpress

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