Stage-Specific Role of Interferon-Gamma in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Abstract

The role of interferon (IFN)-γ in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), has remained as an enigmatic paradox for more than 30 years. Several studies attribute this cytokine a prominent proinflammatory and pathogenic function in these pathologies. However, accumulating evidence shows that IFN-γ also plays a protective role inducing regulatory cell activity and modulating the effector T cell response. Several innate and adaptive immune cells also develop opposite functions strongly associated with the production of IFN-γ in EAE. Even the suppressive activity of different types of regulatory cells is dependent on IFN-γ. Interestingly, recent data supports a stage-specific participation of IFN-γ in EAE providing a plausible explanation for previous conflicting results. In this review, we will summarize and discuss such literature, emphasizing the protective role of IFN-γ on immune cells. These findings are fundamental to understand the complex role of IFN-γ in the pathogenesis of these diseases and can provide basis for potential stage-specific therapy for MS targeting IFN-γ-signaling or IFN-γ-producing immune cells.

Keywords: adaptive immunity; experimental autoimmune encephalomyelitis; innate immunity; interferon-gamma; multiple sclerosis; neuroinflammation.

Figure 1

Dual role of IFN-γ in innate and adaptive immune cells in EAE. (A) Innate immunity: M1-macrophages (M1-MΦ) and natural killer (NK) cells produce interferon (IFN)-γ, which has a pathogenic role exacerbating encephalomyelitis autoimmune experimental (EAE) symptoms. However, some studies have shown that IFN-γ produced by NK and invariant NKT (iNKT) cells inhibits effector Th17 cells, decreasing the disease severity. IFN-γ induces the production of nitric oxide (NO) in neutrophils, MΦ, myeloid-derived suppressor cells (MDSCs), and IFN-γ-induced dendritic cells (IFN-γ-DC). NO can directly inhibit the proliferation of CD4⁺ T cells. IFN-γ also induces the expression of indoleamine 2,3-dioxygenase (IDO) in IFN-γ-DC and arginase-1 (Arg-1) by MDSC, enzymes that can suppress inflammation. Furthermore, IFN-γ induces IL-27 production by mature dendritic cells (mDC) which blocks Th9 differentiation and IL-9 production, controlling disease progression. (B) Adaptive immunity: IFN-γ secreted by Th1 and CD8⁺ T cells has an inflammatory effect and can drive the onset and progression of EAE. Despite this, IFN-γ is able to block Th9 cells, while Th1-secreted IFN-γ inhibits Th2 and Th17 effector cells. Interestingly, IFN-γ can induce CD4⁺CD25⁺ regulatory T cells (Tregs) increasing their FOXP3 expression. Upon transfer, these IFN-γ-induced Tregs limit the severity of EAE. Moreover, IFN-γ production by CD8⁺ regulatory T cells (CD8⁺ Tregs) also reduces EAE symptoms. Finally, IFN-γ produced by γδ T cells worsens EAE, but has a regulatory role on the production of IFN-γ by T cells, which is necessary to limit disease.