Ikaros Sets the Potential for Th17 Lineage Gene Expression through Effects on Chromatin State in Early T Cell Development

Wong, Larry; Hatfield, Julianne K.; Brown, Melissa A.

doi:10.1074/jbc.m113.481440

Cited by 46 publications

(54 citation statements)

References 69 publications

(94 reference statements)

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“…In contrast to our study, a recent report showed that Ikaros positively regulates Th17 cell differentiation (e.g., IL-17 and IL-22 production)(35). The precise reasons underlying this discrepancy are unknown and most likely due to differences in the in vitro culturing conditions, mouse genetic backgrounds, and/or organ(s) assessed in vivo.…”

Section: Discussioncontrasting

confidence: 99%

“…4A, 4B). These data suggest that Ikaros may function as a positive regulator for Ahr transcription, consistent with the direct binding of Ikaros at the Ahr promoter(35). Consistent with the reduced expression of Ahr, Cyp1a1 , a known target gene of Ahr, was downregulated in Ikzf1 ΔF4/ΔF4 CD4 + T cells (Fig.…”

Section: Resultssupporting

confidence: 76%

“…Members of the Ikaros family of transcription factors have been implicated in Treg and Th17 cell differentiation in vitro(35, 42–44). We hypothesized that Ikaros may play an important role in vivo, especially in mucosal tissues where Th17 cells and Tregs are abundantly present.…”

Section: Resultsmentioning

confidence: 99%

“…In CD4 + T cells, Ikaros has been identified as a key regulator for Th1, Th2, and Th17 cell subsets(29, 35, 58, 59), and family members Helios, Eos and Aiolos have been shown to play important roles in the Treg cell compartments(35, 42–44, 60). Our studies uncover a new role for Ikaros in the differential regulation of various Treg compartments (e.g., tTregs, pTregs and iTregs).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, despite thousands of Ikaros-binding sites identified by ChIP-seq, only a small number of genes were found to be either upregulated or downregulated in the absence of full-length wildtype Ikaros (i.e., Ikaros lacking zinc finger 1 or 4) by RNA-seq, suggesting that Ikaros may directly regulate only a limited number of target genes involved in different hematopoietic lineages, developmental stages and biological functions(34). Recent studies have implicated Ikaros in the regulation of different stages of T cell development and in several T cell subsets(28, 30, 35). These studies, taken together, indicate the complex roles of Ikaros in multiple stages of T cell differentiation and function that are still incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Restriction of IL-22–Producing T Cell Responses and Differential Regulation of Regulatory T Cell Compartments by Zinc Finger Transcription Factor Ikaros

Heller

Schjerven

et al. 2014

The Journal of Immunology

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Proper immune responses are needed for controlling pathogen infection at mucosal surfaces. IL-22-producing CD4+ T cells play an important role in controlling bacterial infection in the gut; however, transcriptional regulation of these cells remains elusive. Here, we show that mice with targeted deletion of the fourth DNA-binding zinc finger of the transcription factor Ikaros had increased IL-22- but not IL-17-producing CD4+ T cells in the gut. Adoptive transfer of CD4+ T cells from these Ikaros mutant mice conferred enhanced mucosal immunity against Citrobacter rodentium infection. Despite an intact in vivo thymic-derived Treg compartment in these Ikaros mutant mice, TGF-β, a cytokine well known for induction of Tregs, failed to induce Foxp3 expression in Ikaros mutant CD4+ T cells in vitro but instead promoted IL-22. Aberrant upregulation of IL-21 in CD4+ T cells expressing mutant Ikaros was at least in part responsible for the enhanced IL-22 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor (Ahr), but not RORγt, was required for aberrant IL-22 expression by Ikaros mutant CD4+ T cells, whereas forced expression of Foxp3 was sufficient to inhibit this aberrant cytokine production. Together, our data has uncovered new functions for Ikaros in maintaining mucosal immune homeostasis by restricting IL-22 production by CD4+ T cells.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Restriction of IL-22–Producing T Cell Responses and Differential Regulation of Regulatory T Cell Compartments by Zinc Finger Transcription Factor Ikaros

Heller

Schjerven

et al. 2014

The Journal of Immunology

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Bioinorganic Chemistry of Zinc in Relation to the Immune System

Kepp

2021

ChemBioChem

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Zinc is well‐known to have a central role in human inflammation and immunity and is itself an anti‐inflammatory and antiviral agent. Despite its massively documented role in such processes, the underlying chemistry of zinc in relation to specific proteins and pathways of the immune system has not received much focus. This short review provides an overview of this topic, with emphasis on the structures of key proteins, zinc coordination chemistry, and probable mechanisms involved in zinc‐based immunity, with some focus points for future chemical and biological research.

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

et al. 2019

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The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1β plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1β and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.Keywords: Aiolos r Ikaros r ILC r lenalidomide r NK cells Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Ikaros Sets the Potential for Th17 Lineage Gene Expression through Effects on Chromatin State in Early T Cell Development

Cited by 46 publications

References 69 publications

Restriction of IL-22–Producing T Cell Responses and Differential Regulation of Regulatory T Cell Compartments by Zinc Finger Transcription Factor Ikaros

Restriction of IL-22–Producing T Cell Responses and Differential Regulation of Regulatory T Cell Compartments by Zinc Finger Transcription Factor Ikaros

Bioinorganic Chemistry of Zinc in Relation to the Immune System

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

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