title: Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells.
abstract: Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ability of CD4(+) T cells to differentiate into iTreg diminished markedly with the number of NFAT family members missing. It can be concluded that the expression of Foxp3 in TGF-β-induced iTreg depends on the threshold value of NFAT rather than on an individual member present. This is specific for iTreg development, because frequency of nTreg remained unaltered in mice lacking NFAT1, NFAT2, or NFAT4 alone or in combination. Different from expectation, however, the function of both nTreg and iTreg was independent on robust NFAT levels, reflected by less nuclear NFAT in nTreg and iTreg. Accordingly, absence of one or two NFAT members did not alter suppressor activity in vitro or during colitis and transplantation in vivo. This scenario emphasizes an inhibition of high NFAT activity as treatment for autoimmune diseases and in transplantation, selectively targeting the proinflammatory conventional T cells, while keeping Treg functional.
authors.affiliation: Department of Molecular Pathology, Institute of Pathology,  Julius Maximilians-University Würzburg, 97080 Würzburg,  Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schliesser
authors.forename: Gerd
authors.initials: G
authors.lastname: Müller
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.forename: Kazuki
authors.initials: K
authors.lastname: Satoh
authors.forename: Andrea
authors.initials: A
authors.lastname: Tuettenberg
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Martin R
authors.initials: MR
authors.lastname: Müller
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Sawitzki
authors.forename: Friederike
authors.initials: F
authors.lastname: Berberich-Siebelt
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D003092:Colitis / Q000276:immunology; D016572:Cyclosporine; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D050778:NFATC Transcription Factors / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D050778:NFATC Transcription Factors; D016212:Transforming Growth Factor beta; C064658:RAG-1 protein; D016572:Cyclosporine