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OX40 Gene Expression Is Up-Regulated by Chromatin Remodeling in Its Promoter Region Containing Sp1/Sp3, YY1, and NF-B Binding Sites¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

OX40 is a member of the TNFR superfamily (CD134; TNFRSF4) that is expressed on activated T cells and regulates T cell-mediated immune responses. In this study, we have examined the regulation of OX40 gene expression in T cells. Low-level OX40 mRNA expression was detected in both resting T cells and the nonactivated EL4 T cell line, and was up-regulated in both types of T cells upon activation with anti-CD3 Ab. We have shown in this study that basal OX40 promoter activity is regulated by constitutively expressed Sp1/Sp3 and YY1 transcription factors. NF-B (p50 and p65) also binds to the OX40 promoter region, but the level of direct enhancement of the OX40 promoter activity by this transcription factor is not sufficient to account for the observed up-regulation of OX40 mRNA expression associated with activation. We have detected by chromatin immunoprecipitation that histone H4 molecules in the OX40 promoter region are highly acetylated by activation and NF-B binds to the OX40 promoter in vivo. These findings suggest that OX40 gene expression is regulated by chromatin remodeling, and that NF-B might be involved in initiation of chromatin remodeling in the OX40 promoter region in activated T cells. CD4⁺CD25⁺ regulatory T (Treg) cells also express OX40 at high levels, and signaling through this receptor can neutralize suppressive activity of this Treg cell. In CD4⁺CD25⁺ Treg cells, histone H4 molecules in the OX40 promoter region are also highly acetylated, even in the absence of in vitro activation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants R01 CA74958 (to M.L.T.) and R01 AI31044 (to M.L.T.).

² Address correspondence and reprint requests to Dr. Masahide Tone, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 412 Stellar Chance, 422 Curie Boulevard, Philadelphia, PA 19104-6100. E-mail address: mtone{at}mail.med.upenn.edu

³ Abbreviations used in this paper: OX40L, OX40 ligand; Treg, regulatory T; ChIP, chromatin immunoprecipitation; KO, knockout; UTR, untranslated region; HAT, histone acetyltransferase; HDAC, histone deacetylase.