The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression

Male, Victoria; Nisoli, Ilaria; Kostrzewski, Tomasz; Allan, David; Carlyle, James R.; Lord, Graham M.; Wack, Andreas; Brady, Hugh J.M.

doi:10.1084/jem.20132398

Cited by 165 publications

(186 citation statements)

References 30 publications

(56 reference statements)

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“…Moreover, the expressions of multiple downstream molecules such as EOMES, ID2, GATA3, and IL-15 receptor b (IL-15RB/CD122) have been shown to be regulated by E4BP4. 9,10 ETS1 has also been shown to function at early stages of NK cell development to promote the expression of various transcription factors including T-BET and ID2. 11 In mNK cells, the expression of ETS1 is required for the expression of different NK cell receptors such as NKp46, Ly49H, and Ly49D.…”

Section: Introductionmentioning

confidence: 99%

TOX2 regulates human natural killer cell development by controlling T-BET expression

Vong

Leung

Houston

et al. 2014

Blood

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• Normal maturation of human NK cells requires the expression of TOX2.• TOX2 directly regulates the expression of T-BET during human NK cell development.Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34 1 cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, whereas overexpression of TOX2 enhanced the development of mNK cells from UCB CD34 1 cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation. (Blood. 2014;124(26):3905-3913)

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Section: Introductionmentioning

confidence: 99%

TOX2 regulates human natural killer cell development by controlling T-BET expression

Vong

Leung

Houston

et al. 2014

Blood

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“…1 ILCs may be driven by the transcription factors Nfil3 22 and GATA3, 23,24 respectively ( Figure 2). In this review, we provide an overview of the characteristics of distinct ILC subsets, with emphasis on human ILCs.…”

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confidence: 99%

Human innate lymphoid cells

Hazenberg¹,

Spits

2014

Blood

321

361

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Innate lymphoid cells (ILCs) are lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity and tissue remodeling. ILCs are categorized into 3 groups based on their distinct patterns of cytokine production and the requirement of particular transcription factors for their development and function. Group 1 ILCs (ILC1s) produce interferon γ and depend on Tbet, group 2 ILCs (ILC2s) produce type 2 cytokines like interleukin-5 (IL-5) and IL-13 and require GATA3, and group 3 ILCs (ILC3s) include lymphoid tissue inducer cells, produce IL-17 and/or IL-22, and are dependent on RORγt. Whereas ILCs play essential roles in the innate immune system, uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. In this review, we provide an overview of the characteristics of ILCs in the context of health and disease. We will focus on human ILCs but refer to mouse studies if needed to clarify aspects of ILC biology.

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“…Recently, use of knockout and reporter systems disclosed the presence of distinct NK cell lineages with separate transcription factor expression patterns in mice (10)(11)(12). Conventional mouse NK cells developing in the bone marrow are dependent on E4BP4 and the downstream targets Eomes and Id2 (10,11).…”

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confidence: 99%

Cutting Edge: Identification and Characterization of Human Intrahepatic CD49a+ NK Cells

Marquardt

Béziat

Nyström

et al. 2015

The Journal of Immunology

213

272

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Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a+DX5− NK cells with adaptive-like features. Development of this NK cell lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet+Eomes−CD49a+ NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a+ NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56bright, and express low levels of CD16, CD57, and perforin. After stimulation, CD49a+ NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a+ NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.

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The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression

Abstract: E4bp4 is required for commitment to the NK lineage and promotes NK development by directly regulating the expression of Eomes and Id2.

Cited by 165 publications

References 30 publications

TOX2 regulates human natural killer cell development by controlling T-BET expression

TOX2 regulates human natural killer cell development by controlling T-BET expression

Human innate lymphoid cells

Cutting Edge: Identification and Characterization of Human Intrahepatic CD49a+ NK Cells

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