Interferon-β-driven inflammatory B cells promote TH17-mediated neuro-inflammation

Interferon (IFN)-β is a popular therapy for multiple sclerosis (MS). However, neuro-autoimmune diseases that have strong T Helper (TH) 17 signatures are exacerbated with IFN-β; these includes MS patients who are non-responders to IFN-β and patients with neuromyelitis optica (NMO). Previous studies using experimental autoimmune encephalomyelitis (EAE) demonstrated that IFN-β treatment has exacerbated TH17-induced disease. These results are confounding because one proposed mechanism of the efficacy of IFN-β treatment is that it inhibits IL-17 expression in T-cells. Our objective is to elucidate the conflicting theories on how IFN-β affects TH17 function. Here, we demonstrate that IFN-β enhances the effects of IL-23 on TH17 cells and promotes their pathogenicity by elevating the expression of TH1 and TH17 genes as well as GM-CSF. We next determined the precise cellular mechanism by which IFN-β drives an inflammatory TH17 response. We found that the IFN-β exerts its inflammatory effect by directly acting on B cells which in turn effected the function of T helper cells. Specifically, we found that IFN-β elevates the expression of the co-stimulatory receptors CD80 and CD86 as well as the inflammatory cytokine IL-6 in B-cells. Furthermore, we found that B cells previously stimulated with IFN-β drive the differentiation of myelin-specific TH17 cells, which secrete the inflammatory cytokines GM-CSF, IL-17A, IFNγ and IL-6. Taken together, these findings resolve a mechanistic paradox surrounding type 1 interferon and TH17-induced disease and illuminates possible cellular pathways responsible for the pathophysiology of NMO and of MS patients who are IFN-β non-responders.