title: Nitric oxide modulates TGF-beta-directive signals to suppress Foxp3+ regulatory T cell differentiation and potentiate Th1 development.
abstract: TGF-β can induce Foxp3(+) inducible regulatory T cells (Treg) and also synergize with IL-6 and IL-4 to induce Th17 and Th9 cells. We now report that NO modulates TGF-β activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-β in both IL-12-independent and -dependent fashions by augmenting IFN-γ-activated STAT-1 and T-bet. Differentiation into Treg, Th1, and Th17 lineages could be modulated by NO competing with other cofactors, such as IL-6 and retinoic acid. NO antagonized IL-6 to block TGF-β-directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-β and retinoic acid. Furthermore, we show that physiologically produced NO from TNF and inducible NO synthase-producing dendritic cells can contribute to Th1 development predominating over Treg development through a synergistic activity induced when these cells cocluster with conventional dendritic cells presenting Ag to naive Th cells. This illustrates that NO is another cofactor allowing TGF-β to participate in development of multiple Th lineages and suggests a new mechanism by which NO, which is associated with protection against intracellular pathogens, might maintain effective Th1 immunity.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Heonsik
authors.initials: H
authors.lastname: Choi
authors.forename: So-Young
authors.initials: SY
authors.lastname: Eun
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuyama
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D019070:Cell Lineage / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D051379:Mice; D009569:Nitric Oxide / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide