Abstract
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 down-regulation 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 down-regulation of Runx1 involves negative auto-regulation of the distal Runx1 promoter and contributes to IL-2 production.
Highlights
In naïve cells, Runx1 plays an inhibitory role in the regulation of IL-2 transcription, whereas, in T-cell receptor (TCR)-activated cells, the distal Runx1 promoter appears to be negatively selfregulated by Runx1 itself, resulting in a reduction of Runx1 that contributes to enhanced transcription of IL-2
The present study has demonstrated, firstly, that the regulation of Runx1 via T cell activation occurred at both the RNA and protein levels and, secondly, that TCR-mediated downregulation of Runx1 is a physiological process to permit a higher level of induction of several cytokines including IL-2
(at 6 h), distal Runx1 transcription was suppressed, resulting in the drastic reduction of the overall expression of Runx1 protein. Such differential promoter usage during distal and proximal Runx1 transcription has been reported in mitogen-stimulated T cells and during thymocyte development [29, 30]
Summary
A Runx1-derived protein band could hardly be detected in TCR-stimulated CD4ϩ T cells regardless of the distal/proximal subtype. NFAT over-expression substantially enhanced the activity of an IL-2 promoter-driven reporter that harbors an NFAT site.4 NFAT is not likely to be involved in the TCR-mediated down-regulation of the distal Runx1 promoter.
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