Abstract
Whereas the immune system is essential for host defense against pathogen infection or endogenous danger signals, dysregulated innate and adaptive immune cells may facilitate harmful inflammatory or autoimmune responses. In the CNS, chronic inflammation plays an important role in the pathogenesis of neurodegenerative diseases such as multiple sclerosis (MS). Our previous study has demonstrated a critical role for the type I IFN induction and signaling pathways in constraining Th17-mediated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. However, it remains unknown if self-reactive Th17 cells can be reprogrammed to have less encephalitogenic activities or even have regulatory effects through modulation of innate pathways. In this study, we investigated the direct effects of type I IFN on Th17 cells. Our data show that IFNβ treatment of T cells cultured under Th17 polarizing conditions resulted in reduced production of IL-17, but increased production of IL-10. We also found that IFNβ induced IL-10 production by antigen specific T cells derived from immunized mice. Furthermore, IFNβ treatment could suppress the encephalitogenic activity of myelin-specific T cells, and ameliorate clinical symptoms of EAE in an adoptive transfer model. Together, results from this study suggest that IFNβ may induce antigen-specific T cells to produce IL-10, which in turn negatively regulate Th17-mediate inflammatory and autoimmune response.
Highlights
Accumulating evidence indicates that chronic Inflammation is associated with a variety of human diseases
We demonstrated that IFNb treatment of naıve T cells in Th17 differentiation conditions resulted in decreased expression of IL-17 and RORct
We found that IFNb induced IL-10 production and reduced IL-17 production in antigen specific T cells derived from EAE mice
Summary
Accumulating evidence indicates that chronic Inflammation is associated with a variety of human diseases. Constraining the inflammatory function of immune cells may provide a novel strategy to treat or control many chronic diseases, such as multiple sclerosis (MS) [1,2,3]. Innate immune cells quickly upregulate pro-inflammatory cytokines that serve to initiate host defense against microbial invasion. Excessive inflammation may cause tissue damage and activation of autoreactive T and B cells, which may have deleterious effects on a host. To prevent collateral damage and autoimmunity, hosts develop a number of regulatory mechanisms, including generating Tregs and production of IL-10, to maintain homeostasis of the immune system. During bacterial or viral infection, IL-10 is produced by macrophages and DCs as a negative feedback mechanism to dampen uncontrolled production of inflammatory cytokines. In addition to innate cells, T cells, especially regulatory T cells, are able to produce IL-10 to inhibit the activation of antigen-specific cells and inflammatory response. Studies from other and our groups indicate that type I IFN is able to exert its antiinflammatory role through the induction of IL-10 and IL-27 from macrophages and DCs [9,10,11,12]
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