Transcription factor RORα is critical for nuocyte development

Wong, See Heng; Walker, Jennifer; Jolin, Helen E.; Drynan, Lesley; Hams, Emily; Camelo, Ana Paula; Barlow, Jillian L.; Neill, Daniel R.; Panova, Veera; Koch, Ute; Radtke, Freddy; Hardman, Clare S.; Hwang, You Yi; Fallon, Padraic G.; McKenzie, Andrew N. J.

doi:10.1038/ni.2208

Cited by 531 publications

(624 citation statements)

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“…Downstream of this Id2-dependent progenitor appears to lie an ILC precursor that is dependent on the transcription factor promyelocytic leukaemia zinc finger protein (PLZF) (encoded by Zbtb16), and this progenitor gives rise to ILC1, ILC2, and ILC3, but not classical natural killer (NK) cells or LTi (30) (Figure 1 The timing and duration of Notch signals has also been shown to be critical for lymphoid differentiation and is required for the generation of mouse ILC2 from CLPs in vitro (27). Notch signaling is also important for the generation of human ILC2, and the use of a tuneable intracellular domain of Notch1 indicated that low levels of Notch signaling lead to T-cell TRANSATLANTIC AIRWAY CONFERENCE development, whereas high concentrations lead to ILC2 differentiation (31).…”

Section: Ilc Precursorsmentioning

confidence: 99%

“…In contrast to the more generic ILC commitment factors, the transcription factor RORgt (encoded by Rorc) has been identified as a key regulator of ILC3 cells (10,(32)(33)(34), and RORa has been identified as a key determinant of ILC2 differentiation (27,35). However, even here there is overlap of transcription factor use, with Th17 cells requiring RORgt, and RORa also playing a subordinate role in Th17 cell development.…”

Section: Committed Ilc2mentioning

confidence: 99%

“…ILC2 arise from CLPs in the bone marrow and, like all ILCs, require the transcriptional inhibitor Id2 for their development (7,27,28). This basic helix-loop-helix transcriptional regulator inhibits the activity of the E proteins (29), which have been implicated in the differentiation of B and T cells.…”

Section: Ilc Precursorsmentioning

confidence: 99%

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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: Ilc Precursorsmentioning

confidence: 99%

Section: Committed Ilc2mentioning

confidence: 99%

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Type-2 Innate Lymphoid Cells in Asthma and Allergy

McKenzie

2014

Annals ATS

115

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“…These cells are CD90 (Thy1) + , Sca1 + , CD25 (IL-2Rα) + , CD127 (IL-7Rα) + , and IL-33Rα + . The development of group 2 ILCs is largely dependent on the transcription factors Id2 [12], GATA-3 [15], and RORα [16]; as well as on γc signaling [12,14]. Although the cytokines produced by group 2 ILCs are similar to Th2 cytokines, ILCs are not activated by antigen receptor stimulation and they are widely distributed within various tissues [17].…”

Section: Introductionmentioning

confidence: 99%

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

et al. 2015

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Eosinophils are multifunctional leukocytes involved in allergic reactions as well as adipose tissue regulation. IL-5 is required for eosinophil survival; however, the in vivo mechanisms of eosinophil regulation are not fully understood. A tg mouse model with il5 promoter-driven EGFP expression was established for detecting the IL-5-producing cells in vivo. Il5-egfp tg mice expressed high levels of EGFP in gonadal adipose tissue (GAT) cells. EGFP + cells in GAT were mainly group 2 innate lymphoid cells (ILCs). IL-33 preferentially expanded EGFP + cells and eosinophils in GAT in vivo. EGFP + ILCs were found to upregulate prg2 mRNA expression in GAT eosinophils. These results demonstrate that ILCs activate eosinophils in GAT. The blockage of IL-33Rα, on the other hand, did not impair EGFP + ILC numbers but did impair eosinophil numbers in vivo. GAT eosinophils expressed IL-33Rα and IL-33 expanded eosinophil numbers in CD90 + cell-depleted mice. IL-33 was further observed to induce the expression of retnla and epx mRNA in eosinophils. These findings demonstrate that IL-33 directly activates eosinophils in GAT, and together with our other findings described above, our findings show that IL-33 has dual pathways via which it activates eosinophils in vivo: a direct activation pathway and a group 2 ILCmediated pathway. Keywords: Eosinophils r IL-33 r Innate lymphoid cells r IL-5Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionEosinophils are multifunctional leukocytes involved in the elimination of parasites and the initiation of allergic reactions [1]. Eosinophils secrete major basic protein (MBP, prg2), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin, which damage parasites, and in some cases, damage healthy tissues as well [1]. Eosinophils also play critical roles in metabolic homeostasis relating to obesity [2]. GATA-1 is critical to eosinophil development, and dblGATA mice, in which the GATA binding sites in the Gata1 promoter are mutated, are prone to obesity when fed a high-fat diet [2,3]. Eosinophils are located Correspondence: Associate Prof. Masaaki Hashiguchi e-mail: mhashi@dokkyomed.ac.jp in visceral adipose tissue, and the loss of eosinophils leads to a decrease in alternatively activated macrophage (AAM) accumulation [2]. AAMs in gonadal adipose tissue (GAT) are maintained by . The activation of eosinophils critically depends on IL-5: studies using il5-tg mice or il5-deficient mice and anti-IL-5 Ab have demonstrated that the expansion of eosinophils is largely regulated by . Il5-deficient mice show higher body weight and visceral adipose weight in response to a highfat diet [2]. Deficiency of il5 or eosinophils impairs glucose consumption and promotes obesity [2] and adipose tissue metabolism is thus regulated by eosinophils through the activation of AAMs [2,3,9].Innate lymphoid cells (ILCs) play a protective role against foreign pathogens [10]. ILCs are classified into at least three groups, de...

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“…In this regard, IL-7 is required for the development of all ILC populations with the exception of conventional NK cells and recently described ILC1 populations (Klose et al 2014). By contrast, the retinoic acid receptor-related RORa has been shown to be a key TF solely for ILC2 development as in Rora mutant mice numbers of ILC2, but not other ILC populations, are markedly reduced (Halim et al 2012;Wong et al 2012). Additionally, CLP require IL-33 and Notch signaling to develop into ILC2 in vitro.…”

Section: Development and Ontogeny Of Ilc2mentioning

confidence: 99%

Innate Lymphoid Cells in Type 2 Immune Responses

Mirchandani

Salmond

2014

Arch. Immunol. Ther. Exp.

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In recent years, several distinct innate lymphoid cell populations (ILC) have been characterized in mice and humans. Group 2 ILC function as a rapid responder population in type 2 immune responses. Thus, a wealth of data has implicated an important role for ILC2 in immunity to parasitic infection and in immune pathology in inflammatory and allergic responses. In this review, we describe recent progress in our understanding of the development and ontogeny of ILC2 populations and the mechanisms by which these cells function in a variety of infection and disease settings. Finally, we emphasize recent findings indicating functional interactions between these innate cells and their adaptive CD4 ? Th2 cell counterparts.

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Transcription factor RORα is critical for nuocyte development

Cited by 531 publications

References 50 publications

Type-2 Innate Lymphoid Cells in Asthma and Allergy

Type-2 Innate Lymphoid Cells in Asthma and Allergy

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

Innate Lymphoid Cells in Type 2 Immune Responses

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