Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

Mazzurana, Luca; Forkel, Marianne; Rao, Anna; Acker, Aline Van; Kokkinou, Efthymia; Ichiya, Tamaki; Almér, Sven; Höög, Charlotte; Friberg, Danielle; Mjösberg, Jenny

doi:10.1002/eji.201848075

Cited by 64 publications

(58 citation statements)

References 48 publications

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“…Aiolos promotes NK cell maturation in mice, thus corroborating a role for this transcription factor in the acquisition of a type 1 functional program in a different context 37 . In agreement with our data, a role for Aiolos in human ILC3 to ILC1-like plasticity was very recently reported 38 .…”

Section: Discussionsupporting

confidence: 94%

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Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues

et al. 2019

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Author contributions. C.S., P.L.C and S.Z. contributed equally to this work. M. Cella designed, performed and interpreted experiments. R.G. and S.Z. analyzed scRNA-seq data and wrote methods for scRNA-seq analysis. C.S. generated Aiolos-and T-bet-transduced MNK3 cells. M.L.R. and V.P. analyzed the microarray data and RNA-seq data. K.Z. and M.N.A. provided bioinformatic support. J.K.B., K.Y. and V.C. helped in flow cytometry data presentation and analysis. C.F. and R.F. generated libraries for scRNA-seq. J.S. provided critical advice for Cytof analysis. W.G., L.-L.L. and M.B. provided critical insights to the study. S.G., R.A.F. and L.S. provided key reagents. P.L.C. performed cut and run experiment and interpreted data under supervision of E.M.O. S.A.J. and M. Colonna supervised the study. M. Cella, S.A.J. and M. Colonna wrote the manuscript and all the authors contributed editing and suggestions.

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Section: Discussionsupporting

confidence: 94%

“…It was found that IL-23 enhanced the capacity of TGF-β to induce both Aiolos and T-bet, which may depend on the IL-23-mediated activation of STAT3 and STAT4 (refs. 38,39 ); both have been shown to bind the promoters of Aiolos and Tbet, respectively.…”

Section: Discussionmentioning

confidence: 99%

Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues

et al. 2019

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“…Searching for a functional link between these associated phenomena, it was important to learn that the type-1 cytokine IL-12 not only represents a potent ILC1 activator (44) but also serves as a key inducer of ILC3-to-ILC1 transdifferentiation. In vitro experiments with human tonsillar and fetal gut ILC3s confirmed the plasticity of mature ILC3s, differentiating into IFN-γ-producing ILC1s upon IL-2 and IL-12 stimulation with or without the addition of IL-1β (15,201,203). Moreover, TGF-β was also suggested to induce T-bet expression in stimulated human ILC3s (202).…”

Section: Ilc3 ↔ Ilc1 Plasticitymentioning

confidence: 67%

“…This was further proven in a humanized mouse model: after adoptive transfer of ex vivo expanded IL-22-secreting human ILC3s, an organ-and time-dependent switch to IFN-γ secretion was observed (202). For transition, the transcription factors Aiolos and Ikaros were suggested to shut down the transcription of ILC3 signature genes, thereby allowing the induction of an ILC1-like phenotype and function (202,203).…”

Section: Ilc3 ↔ Ilc1 Plasticitymentioning

confidence: 86%

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

2020

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Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies.

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“…This population expresses CD103, CCR6, and CD300LF to different degrees, with scRNA-seq analysis providing evidence that ILC3s are able to convert in vivo into CD103 + ILC1s. Furthermore, Aiolos (encoded by IKZF3), a member of the Ikaros family of transcription factors, and expressed mainly by ILC1s and NK cells, is critical for skewing ILC3s into CD103 - (22) and intraepithelial CD103 + ILC1s (21). The transcription factor, c-Maf, is also implicated in controlling the homeostatic balance of ILC3s by directly inhibiting T-bet, and therefore transdifferentiation to ILC1s (23,24); in the absence of c-Maf, CD196 -ILC3s transdifferentiate to an ILC1 phenotype (23).…”

Section: Cytokines That Regulate Plasticity Of Lti and Ilc3smentioning

confidence: 99%

Cytokine-Mediated Regulation of Innate Lymphoid Cell Plasticity in Gut Mucosal Immunity

2020

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Mucosal barriers are active sites that encounter a bombardment of antigenic stimuli derived from both the commensal flora and a variety of pathogens, as well as from environmental insults. As such, the ability to mount appropriate innate immune responses is an important first line of defense that confers protection to the host. Central to innate immunity are innate lymphoid cells (ILCs), which were first described a decade ago, and represent a family of heterogeneous cells driven by specific transcription factors and exhibit distinct cytokine profiles that are shared with their CD4+ T-helper cell counterparts. ILCs are particularly enriched at mucosal surfaces, and the tissue microenvironment and cytokine milieu in which ILCs reside are critical factors that drive the behavior and overall function of these cells. In fact, ILCs situated at mucosal barriers must be able to temper their response to a constant exposure of environmental antigens, but also promptly react to pathogens or signals that are potentially harmful to the host. In this context, the ability of ILCs to readily transdifferentiate in response to their dynamic surroundings has become a vigorous area of research, and defining specific mechanism(s) of ILC plasticity is at the advent of discovery. This review will summarize what is currently known regarding the network of cytokines and regulatory elements that enable ILCs to readily transform, based on the range of diverse signals and signal gradients they encounter that lead to either protective or pathogenic function(s), with focus on the gut mucosal immune system.

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Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3−ILC1/NK cell transdifferentiation

Cited by 64 publications

References 48 publications

Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues

Subsets of ILC3−ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Cytokine-Mediated Regulation of Innate Lymphoid Cell Plasticity in Gut Mucosal Immunity

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