The Runx3 Transcription Factor Augments Th1 and Down-Modulates Th2 Phenotypes by Interacting with and Attenuating GATA3

Kohu, Kazuyoshi; Ohmori, Hiroaki; Wong, Won Fen; Onda, Daisuke; Wakoh, Takeshi; Kon, Shunsuke; Yamashita, Masakatsu; Nakayama, Toshinori; Kubo, Masato; Satake, Masanobu

doi:10.4049/jimmunol.0802527

Cited by 66 publications

(65 citation statements)

References 33 publications

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“…The basis for this is a physical interaction between Runx3 and portions of GATA3 that include the N-terminal region and the zinc finger. These observations are confirmed by another report that demonstrates the ability of Runx3 to induce IFN-g production and interact with GATA3 (Kohu et al, 2009). …”

supporting

confidence: 84%

Antisocial Networking in T Helper Cells

Pham

Kaplan

2010

Immunity

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supporting

confidence: 84%

Antisocial Networking in T Helper Cells

Pham

Kaplan

2010

Immunity

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“…Thus, deletion of Runx1 in Treg cells causes a severe autoimmune disease in a mouse model (11)(12)(13). The functions of Runx3 are similar to those of Runx1; Runx3 silences CD4 expression in CD8 single-positive thymocytes (14) and promotes the differentiation of CD4ϩ cells into the Th1 lineage (15)(16)(17).…”

mentioning

confidence: 86%

Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production

Wong

Kurokawa

Satake

et al. 2011

Journal of Biological Chemistry

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Runx1 transcription factor plays multiple roles in T cell development, differentiation, and function. However, the regulatory mechanisms and functional significance of high Runx1 protein expression in resting peripheral CD4؉ T cells is not well understood. Here, we demonstrate that T-cell receptor (TCR) activation down-regulates distal Runx1 transcription, resulting in a significant reduction of Runx1 protein. Interestingly, this downregulation of distal Runx1 transcription appears to be mediated through a negative auto-regulatory mechanism, whereby Runx1 protein binds to a Runx consensus site in the distal promoter. Through the use of Runx1-overexpressing cells from transgenic mice, we demonstrate that interference with TCR-mediated Runx1 down-regulation inhibits IL-2 production and proliferation in activated CD4؉ T cells. In contrast, using Runx1-deficient cells prepared from targeted mice, we show that the absence of Runx1 in unstimulated CD4؉ T cells results in IL-2 derepression. In summary, we propose that high levels of Runx1 in resting CD4؉ T cells functions negatively in the regulation of IL-2 transcription, and that TCR activation-mediated downregulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production.

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“…After 24 h, cells were stimulated with 200 ng/ml PMA and 1 mM ionomycin for 6 h before harvest. Luciferase activity was measured by the Dual-Luciferase Reporter Assay System (Promega), as described (28). pRL-TK (5 ng) was included in each transfection as a normalization control for transfection efficiency.…”

Section: Luciferase Reporter and Chromatin Immunoprecipitation Assaymentioning

confidence: 99%

Runx1 Deficiency in CD4+ T Cells Causes Fatal Autoimmune Inflammatory Lung Disease Due to Spontaneous Hyperactivation of Cells

Wong

Kohu

Nakamura

et al. 2012

The Journal of Immunology

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The Runx1 transcription factor is abundantly expressed in naive T cells but rapidly downregulated in activated T cells, suggesting that it plays an important role in a naive stage. In the current study, Runx1−/−Bcl2tg mice harboring Runx1-deleted CD4+ T cells developed a fatal autoimmune lung disease. CD4+ T cells from these mice were spontaneously activated, preferentially homed to the lung, and expressed various cytokines, including IL-17 and IL-21. Among these, the deregulation of IL-21 transcription was likely to be associated with Runx binding sites located in an IL-21 intron. IL-17 produced in Runx1-deleted cells mobilized innate immune responses, such as those promoted by neutrophils and monocytes, whereas IL-21 triggered humoral responses, such as plasma cells. Thus, at an initial stage, peribronchovascular regions in the lung were infiltrated by CD4+ lymphocytes, whereas at a terminal stage, interstitial regions were massively occupied by immune cells, and alveolar spaces were filled with granular exudates that resembled pulmonary alveolar proteinosis in humans. Mice suffered from respiratory failure, as well as systemic inflammatory responses. Our data indicate that Runx1 plays an essential role in repressing the transcription of cytokine genes in naive CD4+ T cells and, thereby, maintains cell quiescence.

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The Runx3 Transcription Factor Augments Th1 and Down-Modulates Th2 Phenotypes by Interacting with and Attenuating GATA3

Cited by 66 publications

References 33 publications

Antisocial Networking in T Helper Cells

Antisocial Networking in T Helper Cells

Down-regulation of Runx1 Expression by TCR Signal Involves an Autoregulatory Mechanism and Contributes to IL-2 Production

Runx1 Deficiency in CD4+ T Cells Causes Fatal Autoimmune Inflammatory Lung Disease Due to Spontaneous Hyperactivation of Cells

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