Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

Villarino, Alejandro V.; Sciumé, Giuseppe; Davis, Fred P.; Iwata, S.; Zitti, Beatrice; Robinson, Gertraud W.; Hennighausen, Lothar; Kanno, Yuka; O’Shea, John J.

doi:10.1084/jem.20150907

Cited by 80 publications

(141 citation statements)

References 78 publications

(127 reference statements)

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“…As expected, LOF STAT5B mutations cause immunodeficiency . Given its critical role in T cell memory, mutations in the STAT5B gene are associated with recurrent pneumonia and other infections .…”

Section: Genetic Evidence For Criticality Of Jakssupporting

confidence: 52%

“…Like STAT3, STAT5A and STAT5B are also activated by many cytokines including important hematopoietic factors like erythropoietin (EPO) and CSFs. In lymphocytes, STAT5 drives differentiation of innate lymphoid cells, promotes regulatory cell phenotype (Treg) and Foxp3 expression, and inhibits Th17 and follicular helper T cell differentiation …”

Section: Brief Overview Of the Canonical Jak–stat Pathwaymentioning

confidence: 99%

“…These experiments have demonstrated that STATs can bind tens of thousands of sites that include gene promoters and enhancer elements, leading to the modification of chromatin structure. This in turn regulates the transcription not only of protein‐coding genes, but also of microRNAs and long noncoding RNAs . Importantly, nonphosphorylated STATs can also regulate gene expression independently of acute cytokine‐mediated activation .…”

Section: A Paradigm With Important Unknownsmentioning

confidence: 99%

“…Despite their name, STATs both induce and repress genes, though the mechanism for the latter is poorly understood. Finally, STATs have roles in regulating mitochondrial function; given the critical role of cytokines in regulating metabolism, dissecting the transcriptional versus mitochondrial actions of STATs is clearly a key …”

Section: A Paradigm With Important Unknownsmentioning

confidence: 99%

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Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

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124

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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Section: Genetic Evidence For Criticality Of Jakssupporting

confidence: 52%

Section: Brief Overview Of the Canonical Jak–stat Pathwaymentioning

confidence: 99%

Section: A Paradigm With Important Unknownsmentioning

confidence: 99%

Section: A Paradigm With Important Unknownsmentioning

confidence: 99%

See 2 more Smart Citations

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

Self Cite

124

100

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“…Signal transducer and activator of transcription 5 (STAT5; encoded by two adjacent genes, Stat5a and Stat5b ) acts directly downstream of IL‐15 receptor (IL‐15R) signaling on NK cells. Like IL‐15 and IL‐15R, STAT5 is required for NK development and homeostasis, and NK cells are markedly reduced in settings of STAT5 deficiency, with the Stat5b paralog having a greater impact . Early work showed that genetic deletion of Stat5a/b at the NKP‐iNK transition ablated NK cell development at and past the iNK stage.…”

Section: Transcription Factors That Regulate Nk Cell Development Andmentioning

confidence: 99%

Transcriptional control of natural killer cell differentiation

Brillantes

Beaulieu

2018

Immunology

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Summary Natural killer (NK) cells are highly specialized cytotoxic lymphocytes that provide protection against pathogens and malignant cells. They develop from common lymphoid progenitors via a multi‐stage lineage commitment and differentiation process that gives rise to mature NK cells with potent cytotoxic functionality. Although generally considered cells of the innate immune system, recent studies have demonstrated that NK cells have the capacity to mount immune responses with features of adaptive immunity, including robust antigen‐specific clonal‐like expansion and the generation of long‐lived memory cells that mediate enhanced recall responses. Here, we discuss specific transcription factors that have been shown to commonly and uniquely regulate NK cell development and effector and memory responses in experimental mouse models.

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NCR⁺ ILC3 maintain larger STAT4 reservoir via T‐BET to regulate type 1 features upon IL‐23 stimulation in mice

et al. 2018

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Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 toward the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR ILC3) to acquire type 1 features. We observed that NCR ILC3 exhibited high basal expression of the signal-dependent transcription factor STAT4 due to T-BET, leading to predisposed potential for the type 1 response. We found that the prototypical inducer of type 3 response, IL-23, played a predominant role over IL-12 by accessing STAT4 and preferentially inducing its phosphorylation in ILC3 expressing T-BET. The early effector program driven by IL-23 was characterized by the expression of IL-22, followed by a production of IFN-γ, which relies on STAT4, T-BET and required chromatin remodeling of the Ifng locus. Altogether, our findings shed light on a feed-forward mechanism involving STAT4 and T-BET that modulates the outcome of IL-23 signaling in ILC3.

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Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

Abstract: Villarino et al. demonstrate that STAT5 is required for accumulation and function of all ILC subsets in mice. They also define a STAT5-driven transcriptional signature in NK cells and reveal a cooperative relationship with T-bet, another key ILC transcription factor.

Cited by 80 publications

References 78 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Transcriptional control of natural killer cell differentiation

NCR⁺ ILC3 maintain larger STAT4 reservoir via T‐BET to regulate type 1 features upon IL‐23 stimulation in mice

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Subset- and tissue-defined STAT5 thresholds control homeostasis and function of innate lymphoid cells

Abstract: Villarino et al. demonstrate that STAT5 is required for accumulation and function of all ILC subsets in mice. They also define a STAT5-driven transcriptional signature in NK cells and reveal a cooperative relationship with T-bet, another key ILC transcription factor.

Cited by 80 publications

References 78 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Transcriptional control of natural killer cell differentiation

NCR+ ILC3 maintain larger STAT4 reservoir via T‐BET to regulate type 1 features upon IL‐23 stimulation in mice

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NCR⁺ ILC3 maintain larger STAT4 reservoir via T‐BET to regulate type 1 features upon IL‐23 stimulation in mice