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The mechanism underlying suppression of immune responses by interleukin-4 (IL-4) has remained unexplained. Here we show that the antigen-presenting dendritic cell is central to counter-regulation of autoimmune disease by IL-4. IL-4 acts at the locus of the dendritic cell to decrease the cytolytic T-cell response, preventing autoimmunity. Stimulation of cytotoxic precursors by antigen pulsed dendritic cells induces their differentiation but the process is blocked by IL-4. IL-4-influenced DC produce distinct effects on CD8+ T cells depending on their state of activation. The molecular basis for this regulation is the alteration of the expression ratio of the costimulatory ligands B7.1/B7.2 on dendritic cells. Our findings demonstrate that B7.2 induces expansion of CD8+ T cells and B7.1 governs their acquisition of cytolytic activity. IL-4 influences the dendritic cell to elicit qualitative differences in T-cell responses, providing the basis for counter-regulation mediated by IL-4.

Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration. Indeed, we found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also found to be augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated ␤-cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting expansion of precursor cells during pancreas growth.

Immune defense against pathogens often requires NO, synthesized by type 2 NO synthase (NOS2). To discern whether this axis could participate in an autoimmune response, we immunized NOS2-deficient mice with the autoantigen acetylcholine receptor, inducing muscle weakness characteristic of myasthenia gravis, a T cell-dependent Ab-mediated autoimmune disease. We found that the acetylcholine receptor-immunized NOS2-deficient mice developed an exacerbated form of myasthenia gravis, and demonstrated that NOS2 expression limits autoreactive T cell determinant spreading and diversification of the autoantibody repertoire, a process driven by macrophages. Thus, NOS2/NO is important for silencing autoreactive T cells and may restrict bystander autoimmune reactions following the innate immune response.