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Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (RNA)

ABSTRACT: Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a and Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined consensus motifs for dimers versus tetramers. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable, indicating that STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced proliferation and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function.

ORGANISM(S): Mus musculus

PROVIDER: GSE36888 | GEO | 2012/04/25

SECONDARY ACCESSION(S): PRJNA157371

REPOSITORIES: GEO

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Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (RNA)

Project description:Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a and Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined consensus motifs for dimers versus tetramers. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable, indicating that STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced proliferation and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function. T cells were extracted from spleen of wt and STAT5 double knocked in mice, and treated with IL-2. The cells were collected from 0h (without treatment), 2h, 6h and 17h, and chipped on Affy mouse 430 2.0 arrays.

2012-04-24 | E-GEOD-36888 | biostudies-arrayexpress

Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (ChIP-Seq and RNA-Seq)

Project description:Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a and Stat5b double knock-in (DKI) N-domain mutant mice that form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined consensus motifs for dimers versus tetramers. Whereas Stat5- deficient mice exhibited perinatal lethality, DKI mice were viable, indicating that STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+ T cells, NK cells, and CD8+ T cells, with impaired cytokine-induced proliferation and homeostatic proliferation of CD8+ T cells. DKI CD8+ T cell proliferation following viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is dispensable for survival but is critical for cytokine responses and normal immune function. Genome-wide mapping of STAT5A,STAT5B binding in mouse WT and DKI T cells (cultured with or without IL-2 for 1 hr) was conducted. RNA-Seq is conducted in mouse CD8+ T cells (WT and DKI, non-treated or treated with IL-2/IL-15 for 4 hr, 24 hr, 48 hr and 72 hr)

2012-04-25 | E-GEOD-36882 | biostudies-arrayexpress

Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function (ChIP-Seq and RNA-Seq)

2012-04-26 | GSE36882 | GEO

Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells

Project description:Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a-Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8+ T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases. These findings underscore the importance of STAT5 tetramers in maintaining NK cell homeostasis. Moreover, defective STAT5 tetramer formation could represent a cause of NK cell immunodeficiency, and interrupting STAT5 tetramer formation might serve to control NK leukaemia.

2017-09-19 | GSE101470 | GEO

Tetramerization of Transcription Factor STAT5 in Monocytes Promotes Autoimmune-mediated Neuroinflammation via the Regulation of CCL17

Project description:STAT5 plays a critical role in mediating cellular responses following cytokine stimulation. The activated STAT5 proteins can form dimers and tetramers with distinct biological functions. The role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic Th17 cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrated that STAT5 tetramerization regulates the GM-CSF-dependent production of CCL17 by MDCs. Importantly, DKI Th17 cells expanded with CCL17 exhibit more severe EAE. Mechanistically, the effect of CCL17 is dependent on the activity of the integrin VLA-4. Thus, our study uncovered a novel GM-CSF-STAT5 tetramer-CCL17 pathway that promotes autoimmune neuroinflammation via the regulation of Th17 cell migration.

2021-11-30 | GSE181924 | GEO

Essential role of STAT5 tyrosine phosphorylation in vivo

Project description:STAT5 proteins are vital for lymphocyte development and function. Tyrosine phosphorylation of a C-terminal tyrosine is the key event in cytokine activation of STAT5A and STAT5B. However, the role of STAT5 tyrosine phosphorylation has not been assessed in vivo. Here we generated Stat5a and Stat5b tyrosine mutant knock-in (KI) mice and found that these animals had greatly reduced CD8+ T cell numbers. These cells exhibited profoundly diminished proliferation in response to IL-2, correlating with greatly reduced IL-2-induced pRB and a block in the G1-->S phase transition. The mutant cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2R-beta and IL-2R-gamma. Our findings highlight that the tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling and elucidate the molecular basis for achieving an optimal mitogenic effect of IL-2 on CD8+ T cells.

2023-11-06 | MSV000093320 | MassIVE

Essential role of STAT5 tyrosine phosphorylation in vivo

2023-12-23 | MSV000093724 | MassIVE

Regulating Interleukin-2 activity with engineered receptor signaling clamps

Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Genome-wide transcription factors binding of STAT5 and mRNA-Sequencing of gene expression profiles in human pre-activated CD8+ T cells.

2015-06-16 | E-GEOD-64713 | biostudies-arrayexpress

STAT5 tetramerization is a central determinant of monocyte fate and colonic pathogenicity

Project description:In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs, whereas STAT5 tetramer deficiency yields a macrophage phenotype. In the dextran sulfate sodium model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and supplementation with a sustained concentration of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. Thus, this study suggests a protective role of STAT5 tetramers in inflammatory bowel disease through the regulation of arginine metabolism. We previously reported that STAT5 tetramerization in monocytes is detrimental in autoimmune-mediated neuroinflammation. This study highlights the opposing role of STAT5 tetramers in inflammatory bowel disease.

2023-04-11 | GSE207676 | GEO

Stable inhibitory activity of regulatory T cells requires the transcription factor Helios

Project description:The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Treg develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Treg also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. Definition of Helios as a key transcription factor that stabilizes regulatory T-cells in the face of inflammatory responses provides a genetic explanation for a core property of regulatory T-cells. We used microarrays to detail the global programs of gene expression by CD8 Treg (CD44+CD122+Ly49+) and conventional memory type of CD8 cells (CD44+CD122+Ly49-).

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