title: Down-regulation of Runx1 expression by TCR signal involves an autoregulatory mechanism and contributes to IL-2 production.
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.
authors.affiliation: Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Won Fen
authors.initials: WF
authors.lastname: Wong
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kohu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C508594:IL2 protein, human; D007376:Interleukin-2; C493728:RUNX1 protein, human; D011948:Receptors, Antigen, T-Cell; C493726:Runx1 protein, mouse