Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1

Spooner, Chauncey J.; Lesch, Justin; Yan, Donghong; Khan, Aly A.; Abbas, Alex; Ramirez-Carrozzi, Vladimir; Zhou, Meijuan; Soriano, Robert; Eastham-Anderson, Jeffrey; Diehl, Lauri; Lee, Wyne P.; Modrušan, Zora; Pappu, Rajita; Xu, Min; DeVoss, Jason; Singh, Harinder

doi:10.1038/ni.2743

Cited by 161 publications

(174 citation statements)

References 37 publications

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“…Spooner and colleagues have now reported that Gfi1 also alters ILC2 function (41). Using Gfi1-reporter and knockout mice, the authors found that Gfi1 was necessary for IL-33 signaling, but not IL-25.…”

Section: Committed Ilc2mentioning

confidence: 97%

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Type-2 Innate Lymphoid Cells in Asthma and Allergy

McKenzie

2014

Annals ATS

115

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Type-2 innate lymphoid cells (ILC2) belong to an expanding family of innate lymphocytes that provide a potent source of immune effector cytokines at the initiation of immune responses. ILC2 arise, under the control of the transcription factors RORa and GATA3, from lymphoid progenitors in the bone marrow, to secrete type-2 cytokines including IL-5 and IL-13. Using experimental models, ILC2 have been implicated in allergic diseases, such as asthma and atopic dermatitis, but also in metabolic homeostasis. Furthermore, recent reports have indicated that ILC2 not only play roles at the initiation of type-2 immunity but can also contribute to chronic pathology, such as fibrosis, and can impact on the priming of the adaptive T-cell response. The identification of ILC2 in patients with allergic dermatitis and allergic rhinitis indicates that these cells may represent new therapeutic targets.Keywords: type-2 immunity; type-2 innate lymphoid cells; innate immunity; cytokines However, a recent major paradigm shift has added another layer of complexity to immunoregulation by cytokines with the discovery of innate lymphoid cells (ILCs) (2). ILCs produce many Th cell-associated cytokines but do not express cell surface markers associated with other immune cell lineages (lineage-negative [Lin 2 ]) and do not express a T-cell receptor. The ILC family now includes ILC1 (predominantly IFN-g-expressing cells), ILC2 (predominantly IL-5-and IL-13-expressing cells), and ILC3 (predominantly IL-22-and IL-17-expressing cells) (3-6). Due to their recent discovery, our knowledge of these cells is still rather rudimentary, but major roles are emerging for ILCs in protective immunity against parasitic helminths (ILC2) (7-9) and bacteria (ILC1 and ILC3) (10-12), and in autoimmune disorders (ILC1 and ILC3) (13), allergic disease (ILC2) (14-16), and obesity (17)(18)(19).Recent comprehensive reviews have described the identification and phenotypic characterization of 20). This review focuses on the most recent advances in our understanding of the factors that regulate ILC2 development and how these cells contribute to allergy and lung inflammation. ILC2ILC2 are found in the blood, spleen, intestine, liver, lung, fat-associated lymphoid clusters, and lymph nodes of mice (7-9). They are Lin 2 (CD3CD4CD8CD19CD11bCD11cFceR1 NK1.1Gr1 2 ) CD45 1 CD127

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Section: Committed Ilc2mentioning

confidence: 97%

“…Using Gfi1-reporter and knockout mice, the authors found that Gfi1 was necessary for IL-33 signaling, but not IL-25. In the absence of Gfi1, ILC2 uncharacteristically expressed IL-17A as well as IL-13, suggesting that Gfi1 is necessary for repressing the IL-17A pathway (41).…”

Section: Committed Ilc2mentioning

confidence: 99%

Type-2 Innate Lymphoid Cells in Asthma and Allergy

McKenzie

2014

Annals ATS

115

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“…A previous study conducted by Khandanpour showed that the inhibition of Gfi1 can not only cure mice from ALL but also block the expansion of human primary ALL cells [27]. In the immune system, Gfi1 is required for T lymphopoiesis as well as mature CD4+ and CD8+ T cell function and maintenance [28,29]. In addition, Gfi1 has been implicated in the growth and differentiation of various types of cells [30,31,32], and its dysregulation is involved in other solid tumours.…”

Section: Discussionmentioning

confidence: 99%

MiR-495 is a Predictive Biomarker that Downregulates GFI1 Expression in Medulloblastoma

Yun

Zhao

Liu

et al. 2015

Cell Physiol Biochem

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Background: Alterations in the expression level of miR-495 were recently observed in various tumours. Medulloblastoma is the most common malignant brain tumour in children. However, the clinical significance of miR-495 in medulloblastomas remains unclear. Methods: The expression levels of miR-495 was examined in 62 archival formalin-fixed paraffin-embedded (FFPE) medulloblastoma specimens using TaqMan Real-time Quantitative PCR arrays. Immunohistochemistry was used to determine the expression of Gfi1 in medulloblastoma tissues, and a luciferase reporter assay was carried out to confirm whether Gfi1 is a direct target of miR-495. Results: MiR-495 expression is repressed in medulloblastoma samples compared with normal cerebellum tissues. Furthermore, patients with a low level of miR-495 showed significantly poorer survival, as determined by the log-rank test (P = 0.033). The multivariate analysis results showed that the miR-495 expression levels were an independent predictor of overall survival in medulloblastoma patients (P = 0.027; hazard ratio = 0.267). Our study provides the first demonstration that miR-495 directly interacts with the Gfi1 3'UTR to regulate Gfi1 at a post-transcriptional level and that the expression level of miR-495 is inversely correlated with the Gfi1 protein level in medulloblastoma specimens. Conclusion: Our results suggest that miR-495 may be a prognostic predictor in medulloblastoma and that Gfi1 is a potential functional target of miR-495.

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“…B-cell progenitors express both Gfi1 and Gfi1b, 26 but resting peripheral B and T cells do not express readily detectable levels of either Gfi1 or Gfi1b, but Gfi1 levels rise upon antigenic activation in both types of lymphoid cells, 25,34 Gfi1 being particularly important for T helper 2 cells. [35][36][37] Finally, Gfi1 expression has been detected in dendritic cells, and although preliminary data show that it is required for cytokine signaling in this compartment, little is known about the function of Gfi1 or Gfi1b in these cells to date. 38,39 Target genes and gene expression programs A chromatin immunoprecipitation sequencing analysis with murine leukemic cells transduced with a virus directing expression of an MLL-ENL oncofusion protein allowed the identification of Gfi1 target genes.…”

Section: Expression Of Gfi1 and Gfi1b During Normal Hematopoiesismentioning

confidence: 99%

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Möröy

Vaßen

Wilkes

et al. 2015

Blood

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The DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that Gfi1 is primarily important in myeloid and lymphoid differentiation, whereas Gfi1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the Gfi1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of Gfi1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.

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Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1

Cited by 161 publications

References 37 publications

Type-2 Innate Lymphoid Cells in Asthma and Allergy

Type-2 Innate Lymphoid Cells in Asthma and Allergy

MiR-495 is a Predictive Biomarker that Downregulates GFI1 Expression in Medulloblastoma

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

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