MS is a chronic autoimmune demyelinating disease characterized by the infiltration of inflammatory cells, including macrophages and T cells, into the CNS that results in the destruction of myelin sheath (1
). As is the case for most autoimmune diseases, the etiology of MS is not known. The interplay between inflammation and neuronal degeneration most likely contributes to the initiation and progression of CNS tissue damage. To date, there are no curative treatments for MS. However, type I IFN, specifically IFN-β, has proven to be beneficial for the treatment of MS, as demonstrated by decreased inflammatory lesion formation in the CNS, prolonged remission, and lower relapse rate (3
). In contrast, IFN-γ, a type II IFN, appears to exacerbate MS (6
). Although clinical data clearly demonstrate that IFN-β is effective for treating MS, the underlying mechanism responsible for its therapeutic effects remains elusive, and the physiological role of endogenous type I IFNs in inhibiting the development of autoimmune disease is also poorly understood.
MS and EAE, an animal model of MS, were previously thought to be mediated by Th1 cells. However, a number of recent studies provide strong evidence that IL-17–producing T cells play a dominant role in the pathogenesis of EAE (7
). After activation by professional antigen-presenting cells, naive CD4+
T cells differentiate into distinct effector subsets characterized by the cytokines they produce. Traditionally, CD4+
effector T cells have been classified into 2 subsets: Th1 and Th2 lineages. Th1 cells are induced by IL-12 and produce large quantities of IFN-γ, whereas Th2 cells secrete IL-4, IL-5, and IL-13. While Th1 cells orchestrate cellular immunity, Th2 cells regulate humoral immunity and allergic response. In addition, Tregs have been identified for their ability to control effector T cell responses. Recently, a new Th subset that produces IL-17 (Th17) was identified. Th17 cells are distinct from Th1 and Th2 cells in phenotype, function, and developmental pathways. Th17 cells have been shown to play a critical role in the pathogenesis of inflammatory diseases, such as adjuvant-induced arthritis and EAE (7
The development of Th17 cells is regulated by a complex network of cytokines. A number of studies demonstrate that the differentiation of Th17 cells depends on TGF-β and IL-6, which induce naive T cells to secrete IL-21. IL-21 in turn functions in a positive autocrine loop to upregulate Th17 lineage–specific transcription factor RORγt and expression of IL-17, whereas IL-23 maintains and expands the Th17 cell populations (10
). Interestingly, TGF-β is also essential for the generation of Foxp3+
Tregs. Reciprocal development pathways for the generation of pathogenic Th17 cells and Foxp3+
Tregs have therefore been proposed. While TGF-β alone promotes the generation of Tregs that are well known for their ability to suppress autoimmunity and inflammation, in the presence of IL-6 produced by the innate immune system during infection, TGF-β induces the differentiation of proinflammatory Th17 cells. In addition to IL-6 and TGF-β, other cytokines, including IL-1, IL-13, IL-18, IL-22, and TNF, have been shown to promote Th17 differentiation or expansion in combination with IL-6/TGF-β or IL-23 (16
). Studies also demonstrate that certain cytokines can interfere with the development of Th17 cells. IL-4, IFN-γ, and IFN-α are found to inhibit IL-23–driven expansion of Th17 cells. IL-2, a cytokine important for T cell survival and generation of Foxp3+
Tregs, inhibits the differentiation and/or expansion of Th17 cells (33
). Furthermore, IL-27, an IL-12/IL-23 family member, is a potent negative regulator of Th17 cell differentiation (34
). IL-27 is a heterodimeric molecule composed of p28 and Epstein-Barr virus–induced gene 3 (Ebi3
) subunits, which have homologies to IL-12p35 and p40 respectively. The IL-27 receptor complex consists of the unique subunit IL-27R and the gp130 chain of IL-6R. IL-27 is produced by innate immune cells and has various effects on T cell immunity. Recent data show that IL-27, via STAT1 signaling, can inhibit the differentiation of Th17 cells triggered by IL-6 plus TGF-β (34
). Loss of IL-27 expression leads to increased Th17 differentiation, enhanced infiltration of IL-17–producing T cells in inflamed tissues, and exacerbated neuroinflammation.
Clinical studies demonstrate that MS is a T cell–mediated autoimmune disease of the CNS, which indicates that tolerance to the self antigen myelin is broken down, leading to the activation of autoreactive T cells. However, the existence of autoreactive T cells is not the only factor in the initiation and development of MS. Although myelin-reactive T cells are also present in healthy individuals, normal individuals have multiple layers of protective mechanisms to suppress the activation of autoreactive T cells. In EAE, the disease is induced peripherally by injection of self antigen in association with a strong adjuvant containing killed whole mycobacteria. Thus, TLRs play an important role by inducing inflammatory cytokine milieu, which may promote Th17 development and contribute to the pathogenesis of autoimmune disease. TLR signaling is mediated by a family of MyD88 adaptor proteins, primarily MyD88 and Toll–IL-1 receptor domain–containing adaptor inducing IFN-β (TRIF) (40
). We and others have identified 2 major types of TLR signaling pathways: the MyD88-dependent activation of NF-κB, which results in the induction of inflammatory genes such as TNF, IL-6, and IL-1β; and TRIF-dependent pathways involving the induction of type I IFNs and secondary response genes activated by IFN-β in an autocrine/paracrine manner (40
). The type I IFN family consists of IFN-β and multiple IFN-α subtypes. These cytokines bind to a common receptor, the type I IFN receptor (IFNAR), leading to the activation of the JAK/STAT signaling pathway. In addition to their well-known function as the first line of defense against viral infection, type I IFNs have a variety of immunomodulatory effects on DCs, macrophages, T cells, and B cells. Recently, we found that the production of and signaling by type I IFN is required for LPS-induced IL-10 upregulation, suggesting that the type I IFN pathway may serve a novel antiinflammatory role in TLR-mediated signaling in macrophages (44
Since the identification of IL-17–producing cells, extensive studies have been performed to investigate the development and function of Th17 cells. There are also multiple studies that examine the association of these cells with autoimmune diseases, including EAE. However, the contribution of innate immunity to the development of the Th17 lineage has not been well characterized. Furthermore, the functional role of type I IFN induction pathways in modulating inflammatory response in EAE is not fully understood. In this study, we used EAE as a model to investigate the role of the TRIF-dependent IFN induction pathway of the innate immunity system in the regulation of autoimmune inflammation. Our results demonstrate that the TRIF pathway negatively regulates Th17-mediated autoimmune inflammation via type I IFN–induced IL-27 production in macrophages.