Transcription factor IRF8 controls Th1-like regulatory T-cell function

Lee, Wonyong; Kim, Hyeong Su; Baek, Song Yi; Lee, Gap Ryol

doi:10.1038/cmi.2015.72

Cited by 42 publications

(37 citation statements)

References 36 publications

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“…The interferon regulatory factor family has been broadly identified as an important regulator in the differentiation of T helper cells [8]. Irf8 À/À Treg cells were recently shown to unable to suppress effector T cells [10]. However, the post-transcriptional modification of IRF8 is not fully characterized.…”

Section: Discussionmentioning

confidence: 99%

“…IRF8, induced by TCR engagement in T cells, exerts an influence on the differentiation of T helper cells [9]. Treg cells derived from Irf8 À/À mice exhibit aberrant expression of Il4 and Il17 as well as an impairment of suppressive function to regulate the Th1 response [10]. In addition, it has been shown that the function of IRF8 could be precisely regulated at the transcriptional level [11].…”

Section: Abstract: Irf8; Regulatory T Cells; Usp4mentioning

confidence: 99%

“…In the present study, we were interested in the potential role of USP4 in Treg cells. Given that Irf8 À/ À Treg cells exhibit an impairment of suppressive function [10], we intended to investigate whether the protein stability and activity of IRF8 is also regulated by protein post-translational modification enzymes such as USP4. We first set out to examine whether USP4 could interact with IRF8.…”

Section: Usp4 Interacts With Irf8mentioning

confidence: 99%

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USP4 interacts and positively regulates IRF8 function via K48‐linked deubiquitination in regulatory T cells

et al. 2017

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CD4 CD25 regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells.

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Irf8; Regulatory T Cells; Usp4mentioning

confidence: 99%

Section: Usp4 Interacts With Irf8mentioning

confidence: 99%

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USP4 interacts and positively regulates IRF8 function via K48‐linked deubiquitination in regulatory T cells

et al. 2017

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“…It regulates many critical elements, including the differentiation of monocytes/dendritic cells, the production of IFNγ from T cells and IL-12 from myeloid cells, the transcriptional response to these cytokines, and the relevant polarization of T cells [49–51]. The central role of IRF8 illustrates the concept that single immune genes determine the response to specific classes of pathogen by coordinating multiple pathways in many different cell types.…”

Section: Dendritic Cells In Primary Immunodeficiency Diseasementioning

confidence: 99%

Dendritic cell analysis in primary immunodeficiency

Barge

Collin

2016

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewDendritic cells are specialized antigen-presenting cells which link innate and adaptive immunity, through recognition and presentation of antigen to T cells. Although the importance of dendritic cells has been demonstrated in many animal models, their contribution to human immunity remains relatively unexplored in vivo.Given their central role in infection, autoimmunity, and malignancy, dendritic cell deficiency or dysfunction would be expected to have clinical consequences.Recent findingsHuman dendritic cell deficiency disorders, related to GATA binding protein 2 (GATA2) and interferon regulatory factor 8 (IRF8) mutations, have highlighted the importance of dendritic cells and monocytes in primary immunodeficiency diseases and begun to shed light on their nonredundant roles in host defense and immune regulation in vivo. The contribution of dendritic cell and monocyte dysfunction to the pathogenesis of primary immunodeficiency disease phenotypes is becoming increasingly apparent. However, dendritic cell analysis is not yet a routine part of primary immunodeficiency disease workup.SummaryWidespread uptake of dendritic cell/monocyte screening in clinical practice will facilitate the discovery of novel dendritic cell and monocyte disorders as well as advancing our understanding of human dendritic cell biology in health and disease.

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“…One such example is the myeloid TF Interferon Regulatory Factor 8 (IRF8), which plays a key role in myelopoiesis and maintaining the critical balance of the major myeloid subsets (6). Additionally, IRF8 is part of a regulatory complex involved in specification and commitment to B-cell development (7) and controls T-cells functions and activities (8, 9). Aberrant expression of this Interferon-γ (IFNγ) - induced gene (10) is associated with skewed differentiation, which is accompanied by myeloleukemias (11-13).…”

Section: Introductionmentioning

confidence: 99%