Abstract

Type I IFNs (IFN-a and IFN-ß) and type II IFN (IFN-?) mediate both regulation and inflammation in multiple sclerosis, neuromyelitis optica, and in experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for these Janus-like activities of type I and II IFNs in neuroinflammation remains unclear. Although endogenous type I IFN signaling provides a protective response in neuroinflammation, we find that when IFN-? signaling is ablated, type I IFNs drive inflammation, resulting in exacerbated EAE. IFN-? has a disease stage-specific opposing function in EAE. Treatment of mice with IFN-? during the initiation phase of EAE leads to enhanced severity of disease. In contrast, IFN-? treatment during the effector phase attenuated disease. This immunosuppressive activity of IFN-? required functional type I IFN signaling. In IFN-a/ß receptor-deficient mice, IFN-? treatment during effector phase of EAE exacerbated disease. Using an adoptive transfer EAE model, we found that T cell-intrinsic type I and II IFN signals are simultaneously required to establish chronic EAE by encephalitogenic Th1 cells. However, in Th17 cells loss of either IFN signals leads to the development of a severe chronic disease. The data imply that type I and II IFN signals have independent but nonredundant roles in restraining encephalitogenic Th17 cells in vivo. Collectively, our data show that type I and II IFNs function in an integrated manner to regulate pathogenesis in EAE.

View details for DOI 10.4049/jimmunol.1300419

View details for Web of Science ID 000324206900014

View details for PubMedID 23960239

View details for PubMedCentralID PMC3779698