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

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2007; 179(3):1760-7. DOI: 10.4049/jimmunol.179.3.1760
Source: PubMed


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-kappaB (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-kappaB binds to the OX40 promoter in vivo. These findings suggest that OX40 gene expression is regulated by chromatin remodeling, and that NF-kappaB 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.

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    • "(A) Shown is the sequence of the Mina P1 promoter mapped to region (−64/+19) showing the TSS (bent arrow), the four consensus Sp1/3 binding sequences (boxed and shaded), and probes p1–p4 each containing a single Sp1/3 site (underlined and labeled). (B) Representative EMSA assay showing nucleoprotein complexes 1 and 2 (arrows) formed by combining nuclear extracts from EL4 cells with 5′ biotin labeled probes p1–p4 in the absence or presence of a 100-fold molar excess of unlabeled probes containing autologous (p1–p4) and heterologous (A and B corresponding to Sp1A and Sp1B, respectively, from the OX40 promoter [16]) Sp1/3 consensus sequences. Data are representative of 2 experiments. "
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    • "To this end, we have identified putative STAT3 and STAT5-binding sites in the OX40 promoter and are beginning to elucidate the transcriptional machinery regulating OX40 expression. It should be noted that Sp1/Sp3/YY1 transcription factors can regulate the basal OX40 promoter, however this work did not address the role of gc/STAT-mediated signaling in driving OX40 expression [45]. "
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