HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nakano, N. Articles by Hozumi, N. Search for Related Content PubMed PubMed Citation Articles by Nakano, N. Articles by Hozumi, N.

NF-AT-Mediated Expression of TGF-1 in Tolerant T Cells¹

Research Institute for Biological Sciences, Tokyo University of Science, Chiba, Japan

During T cell development in the thymus, a certain population of self-reactive thymocytes differentiates into regulatory T cells that suppress otherwise harmful self-reactive T cells. In transgenic mice expressing both TCR that specifically recognizes moth cytochrome c and the moth cytochrome c ligand, a large proportion of CD4⁺ T cells expresses CD25 and secretes TGF-1 upon Ag stimulation. Because TGF-1 expression by these T cells can be decreased by cyclosporin A, a NF-AT inhibitor, NF-AT-mediated TGF-1 expression in T cells was addressed by characterizing a NF-AT response element in the TGF-1 promoter. Analysis of the mouse TGF-1 promoter (–1799 to +793) in transfection experiments in T cell 68-41 hybridoma cells detected NF-AT binding sites at positions +268 and +288 in the proximal promoter region. Binding of NF-AT to this region was detected only in tolerant CD4⁺ T cells, but not in fully activated CD4⁺ T cells by chromatin immunoprecipitation assays. Activation of these NF-AT sites was sufficient to induce TGF-1 promoter activity; however, additional signaling due to full Ag stimulation blocked NF-AT-mediated TGF-1 expression. This suppression of the TGF-1 promoter is mediated by the –1079 to –406 region, in which deletion of a GATA-binding motif at position –821 abrogates NF-AT-mediated activation of the TGF-1 promoter. Therefore, TGF-1 expression in T cells is controlled by multiple regulatory factors that have distinct functions in response to partial or full TCR 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 by grants from the Ministry of Education, Science, Sports and Culture of the Government of Japan (to N.N.).

² Address correspondence and reprint requests to Dr. Naoko Nakano, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan. E-mail address: naoko{at}rs.noda.tus.ac.jp

³ Current address: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

⁴ Current address: Department of Pathology and Center of Immunology, Washington University School of Medicine, Howard Hughes Medical Institute, St. Louis, Missouri 63110.

⁵ Abbreviations used in this paper: MCC, moth cytochrome c; -Gal, -galactosidase; CA, constitutively active; ChIP, chromatin immunoprecipitation; CsA, cyclosporin A; HPRT, hypoxanthine phosphoribosyltransferase.