Stat5 gene dosage in T cells modulates CD8<sup>+</sup>T-cell homeostasis and attenuates contact hypersensitivity response in mice

Nivarthi, Harini; Prchal-Murphy, Michaela; Swoboda, Alexander; Hager, Martin H.; Schlederer, Michaela; Kenner, Lukas; Tuckermann, Jan; Sexl, Veronika; Moriggl, Richard; Ermakova, Olga

doi:10.1111/all.12535

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…Thus, the differences in b-catenin expression levels in the same mouse model can either result in the block of T cell development at the DP stage, causing a predisposition to leukemia (33), or they can initiate the development of an autoimmune/inflammatory disease in the CNS (as in the current study). Although both models showed a survival These data highlight the previously reported importance of b-catenin expression levels for its biological activity (32,47), which has also been observed for other transcription factors (48,49).…”

Section: Discussionsupporting

confidence: 81%

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

Sorcini

Bruscoli

Frammartino

et al. 2017

The Journal of Immunology

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The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4 T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

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Section: Discussionsupporting

confidence: 81%

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

Sorcini

Bruscoli

Frammartino

et al. 2017

The Journal of Immunology

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“…Despite the Vav1 promoter–dependent expression of hSTAT5B N642H throughout the entire hematopoietic system, malignancy evolved in CD8 + T cells. This development could be a result of the CD8 + T cell sensitivity to the Stat5a/b gene dosage that was described previously in mice ( 62 ). Moreover, it has been reported that CD8 + T cells are more susceptible to oncogenic drivers, especially when these drivers are activated by cytokines or triggered via T cell receptors ( 62 , 63 ).…”

Section: Discussionsupporting

confidence: 56%

STAT5BN642H is a driver mutation for T cell neoplasia

Phạm

Maurer

Prchal-Murphy

et al. 2017

Journal of Clinical Investigation

107

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STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.

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“…The idea that STAT5 concentration can impact cellular function also has precedent. Of particular interest are studies reporting severe immunological phenotypes in transgenic mice which over-express STAT5A or STAT5B ( Kelly et al, 2003a ; Kelly et al, 2003b ), and studies showing that Stat5a/b haplo-insufficiency ameliorates contact hypersensitivity ( Nivarthi et al, 2014 ). In addition, we have previously demonstrated that ectopic STAT5A can expand the target repertoire of STAT5 in mouse embryonic fibroblasts ( Zhu et al, 2012 ), and have explored the concept of STAT5 gene dosage in the context of mammary development, finding that a high STAT5 threshold must be reached for mammary epithelial cell differentiation ( Yamaji et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

Villarino

Robinson

Bonelli

et al. 2016

eLife

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The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology.DOI: http://dx.doi.org/10.7554/eLife.08384.001

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Stat5 gene dosage in T cells modulates CD8⁺T-cell homeostasis and attenuates contact hypersensitivity response in mice

Abstract: Our data identify Stat5 as a dose-dependent regulator of CD8(+) T-cell functions in contact allergies and suggest that modulation of Stat5 dosage could be used to target contact allergies in humans.

Cited by 10 publications

References 47 publications

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

STAT5BN642H is a driver mutation for T cell neoplasia

Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

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Stat5 gene dosage in T cells modulates CD8+T-cell homeostasis and attenuates contact hypersensitivity response in mice

Abstract: Our data identify Stat5 as a dose-dependent regulator of CD8(+) T-cell functions in contact allergies and suggest that modulation of Stat5 dosage could be used to target contact allergies in humans.

Cited by 10 publications

References 47 publications

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

STAT5BN642H is a driver mutation for T cell neoplasia

Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

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Stat5 gene dosage in T cells modulates CD8⁺T-cell homeostasis and attenuates contact hypersensitivity response in mice