Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4<sup>+</sup>T cells

Honma, Kiyonobu; Kimura, Daisuke; Tominaga, Norio; Miyakoda, Mana; Matsuyama, Tomohiro; Yui, Katsuyuki

doi:10.1073/pnas.0803171105

Cited by 44 publications

(27 citation statements)

References 38 publications

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“…Because IRF4 is indispensible for the development of Th9 cells, it is notable that IRF4-deficient mice are incapable of expelling N. brasiliensis (Honma et al, 2008). This suggests that protective IL-9 production presumably by Th9 cells is lacking in the absence of IRF4.…”

Section: T Cells Correlates With Irf4 Expressionmentioning

confidence: 97%

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

Bothur²,

et al. 2010

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Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4(+) T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.

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Section: T Cells Correlates With Irf4 Expressionmentioning

confidence: 97%

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

Bothur²,

et al. 2010

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“…Notably, similar dual function in cytokine gene control has recently been shown for IRF4, which regulated Th2 cytokine production, especially IL-4, differentially in naive CD4 ϩ cells compared with effector/memory CD4 ϩ cells. 45 The 5Ј flanking region of the human IL-5 gene has been reported to interact with many transcription factors, including GATA3, NFAT, YY1, and glucocorticoid receptor, which play important roles in IL-5 expression. 35,37,46 Our in vitro binding assay demonstrated that SATB1 binds 4 sites on the human IL-5 promoter.…”

Section: Discussionmentioning

confidence: 99%

SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

Ahlfors

Limaye

Elo

et al. 2010

Blood

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“…In B cells, the strength of B-cell receptor signaling determines the level of IRF4 protein produced; in turn, this graded expression of IRF4 regulates memory B-cell vs. plasma cell lineage development (13,14). IRF4 is also required for T-cell function and is essential for T helper (Th) 2, Th9, and Th17 CD4 + lineage development (15)(16)(17)(18)(19)(20)(21)(22)(23). In addition to the role of IRF4 in effector CD4 + T-cell differentiation, IRF4 is important in Foxp3 + regulatory T cells (T-regs), because Irf4 −/− T-regs are unable to suppress spontaneous T-cell activation in vivo (24).…”

Section: Cd8mentioning

confidence: 99%

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

Nayar

Enos

Prince

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

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CD8 + T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of “innate” T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8 + T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8 + T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8 + T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8 + T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8 + T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8 + T cells.

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Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4⁺T cells

Cited by 44 publications

References 38 publications

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation

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Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4+T cells

Cited by 44 publications

References 38 publications

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

Interferon-Regulatory Factor 4 Is Essential for the Developmental Program of T Helper 9 Cells

SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 + T-cell differentiation

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Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4⁺T cells

TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8 ⁺ T-cell differentiation