Nitric Oxide Modulates TGF-beta-Directive Signals To Suppress Foxp3(+) Regulatory T Cell Differentiation and Potentiate Th1 Development

Abstract

TGF-beta 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-beta activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-beta in both IL-12-independent and -dependent fashions by augmenting IFN-gamma-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-beta-directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-beta 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-beta 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. The Journal of Immunology, 2011, 186: 6972-6980.