Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

Geiger, Theresa L.; Abt, Michael C.; Gasteiger, Georg; Firth, Matthew A.; O'Connor, Margaret; Geary, Clair D.; O’Sullivan, Timothy E.; Brink, Marcel R. van den; Pamer, Eric G.; Hanash, Alan M.; Sun, Joseph C.

doi:10.1084/jem.20140212

Cited by 223 publications

(197 citation statements)

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“…[42][43][44] Nfil3-deficient mice display a severe defect in NK-cell development, 45,46 in addition to impaired development of CD8 1 and CD103 1 conventional DC subsets, B cells, and other innate lymphoid subsets. 44,[47][48][49] Reduced GATA-2-mediated induction of NFIL-3 could thus contribute to DC, B-cell, and NK-cell cytopenias observed in humans with GATA-2 haploinsufficiency, as suggested by our findings of reduced NK-cell output from Lin 2 cell progenitors in patients with GATA2 mutation. Interestingly, CMV infection bypasses the requirement for Nfil3 in mouse NK-cell development, supporting generation of long-lived, adaptive NK cells.…”

Section: Discussionmentioning

confidence: 56%

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Schlums

Jung

Han

et al. 2017

Blood

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Section: Discussionmentioning

confidence: 56%

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Schlums

Jung

Han

et al. 2017

Blood

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“…They require RORγt TF and, as recently suggested, may also require E4BP4 TF for their development. They reside in MALT and in secondary lymphoid organs, provide host defenses against extracellular pathogens, and contribute to tissue remodeling [19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors

et al. 2015

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NK cells are innate lymphocytes characterized by the expression of nuclear factor interleukin 3 regulated (NFIL3 or E4BP4), eomesodermin (EOMES) transcription factors (TFs), and by the ability to exert cytolytic activity and release IFN-γ. In the haploidenticalhematopoietic stem cell transplantation (haplo-HSCT) setting, CD34 + donor derived NK cells play a major role in the control of leukemic relapses. Therefore, it is important to better define cytokines that influence NK-cell differentiation from CD34 + precursors. We analyzed the effects of IL-1β on NK-cell differentiation from umbilical cord blood (UCB) CD34 + cells. While IL-1β inhibited CD161 + CD56 + cell proliferation, an increased expression of LFA-1, CD94/NKG2A, KIRs, and perforin on CD56 + cells was detected. In addition, within the CD161 + CD56 + IL-1RI + LFA-1 − cell fraction (representing group 3 innate lymphoid cells, ILC3-like cells), a significant increase of EOMES, NKp46, and CD94/NKG2A receptors, cytolytic granules, and IFN-γ was detected. This increase was paralleled by a decrease of related orphan receptors (RORγt) TF, NKp44 expression, and IL-22 production. These data suggest that IL-1β inhibits ILC3-while favoring NK-cell maturation. Since in haplo-HSCT conditioning regimen, infections or residual leukemia cells may induce IL-1β production, this may influence the NK/ILC3 development from donor-derived CD34 + precursors.Keywords: IL-1β r ILC3 r Innate immunity r NK cells r NK-cell development Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNatural killer (NK) cells are major effectors of the innate immunity. They are able to rapidly eliminate virally infected cells or tumor cells [1][2][3]. Their activity is finely regulated by a number of activating and inhibitory receptors that tune their cytolytic Correspondence: Dr. Chiara Vitale e-mail: chiara.vitale@unige.it activity and cytokine secretion [4,5]. The main activating receptors include NKp46, NKp30, and NKp44 (collectively termed natural cytotoxicity receptors), NKG2D, and DNAM-1 [6,7]. In addition, NK cells express inhibitory receptors specific for HLA class I molecules, including killer immunoglobulin-like(Ig-like) receptors (KIRs), specific for allotypic HLA class I determinants, and * These authors contributed equally to this work as senior co-authors. Eur. J. Immunol. 2015Immunol. . 45: 2061Immunol. -2071 CD94/NKG2A specific for 9]. NK cells are characterized by production of IFN-γ and the expression of cytolytic granules. Their development requires the expression of E4BP4 (NFIL3, nuclear factor interleukin 3), Tbx21 (T-bet), eomesodermin (EOMES) transcription factor (TF) [10][11][12][13][14] and occurs primarily in the BM, proceeding through a multistep process characterized by the sequential acquisition of markers/receptors (including CD117, CD161, CD56, CD94/NKG2A, LFA-1, CD16, and KIRs) and functions [10,11,15]. NK cells are developmentally related to innate lymphoid cells (ILCs) as they derive fro...

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“…A subsequent study revealed that Nfil3 was only required in early progenitor cells and that deletion at the NKP stage (when NKp46 is first expressed) or in mature NK cells surprisingly did not impact total NK cell numbers, function, or response against viral infection (Firth et al 2013). Consistent with this finding, CLP numbers are normal in the Nfil3-deficient mice, and numbers begin to decline as NKPs transition to the iNK stage (Gascoyne et al 2009;Geiger et al 2014). Nfil3 is expressed as early as the CLP stage (and possibly earlier) where it promotes NK cell lineage commitment by directly regulating the expression of Eomes and Id2 , and thus, Id2 overexpression could rescue NK cell development in the setting of Nfil3-deficiency (Gascoyne et al 2009;Male et al 2014).…”

Section: Generation Of An Nk Cell From a Common Lymphoid Progenitormentioning

confidence: 83%

Transcriptional Control of NK Cells

Sun

2015

Natural Killer Cells

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Natural killer (NK) cells are innate lymphocytes that survey the environment and protect the host from infected and cancerous cells. As their name implies, NK cells represent an early line of defense during pathogen invasion by directly killing infected cells and secreting inflammatory cytokines. Although the function of NK cells was first described more than four decades ago, the development of this cytotoxic lineage is not well understood. In recent years, we have begun to identify specific transcription factors that control each stage of development and maturation, from ontogeny of the NK cell progenitor to the effector functions of activated NK cells in peripheral organs. This chapter highlights the transcription factors that are unique to NK cells, or shared between NK cells and other hematopoietic cell lineages, but govern the biology of this cytolytic lymphocyte.

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Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

Abstract: Nfil3 is critical for normal development of innate lymphoid cell (ILC) progenitors. Nfil3-deficient mice have severely reduced lung and visceral adipose tissue ILC2s and gut-associated ILC3s, and compromised innate immunity to acute bacterial infection.

Cited by 223 publications

References 64 publications

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors

Transcriptional Control of NK Cells

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Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

Abstract: Nfil3 is critical for normal development of innate lymphoid cell (ILC) progenitors. Nfil3-deficient mice have severely reduced lung and visceral adipose tissue ILC2s and gut-associated ILC3s, and compromised innate immunity to acute bacterial infection.

Cited by 223 publications

References 64 publications

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34+ precursors

Transcriptional Control of NK Cells

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IL‐1β inhibits ILC3 while favoring NK‐cell maturation of umbilical cord blood CD34⁺ precursors