title: NF-AT-mediated expression of TGF-beta1 in tolerant T cells.
abstract: 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-beta1 upon Ag stimulation. Because TGF-beta1 expression by these T cells can be decreased by cyclosporin A, a NF-AT inhibitor, NF-AT-mediated TGF-beta1 expression in T cells was addressed by characterizing a NF-AT response element in the TGF-beta1 promoter. Analysis of the mouse TGF-beta1 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-beta1 promoter activity; however, additional signaling due to full Ag stimulation blocked NF-AT-mediated TGF-beta1 expression. This suppression of the TGF-beta1 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-beta1 promoter. Therefore, TGF-beta1 expression in T cells is controlled by multiple regulatory factors that have distinct functions in response to partial or full TCR activation.
authors.affiliation: Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan. naoko@rs.noda.tus.ac.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Nakano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hosokawa
authors.forename: Masako
authors.initials: M
authors.lastname: Kohyama
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Hozumi
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006825:Hybridomas; D007108:Immune Tolerance / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020218:Response Elements / Q000276:immunology; D017384:Sequence Deletion; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
chemical_list: D000941:Antigens; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine