IFN-β suppresses GM-CSF production by CD4+ T cells by inhibiting STAT5 signaling

Abstract

Abstract Multiple sclerosis (MS) is an autoimmune disease characterized by accumulation of immune cells in the central nervous system (CNS). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary for development of CNS autoimmunity in animal models of MS, suggesting that GM-CSF also plays an important role in the pathogenesis of MS. We previously reported that untreated MS patients have higher frequencies of GM-CSF+ CD4+ T cells in their peripheral blood, and that IFN-β therapy normalized their numbers. Since IFN-β suppresses GM-CSF expression by CD4+ T cells in MS, we sought to determine the mechanisms of its action. It has been shown that IFN-β activates multiple JAK/STAT signaling pathways in T cells, and that GM-CSF expression in T cells is largely dependent on STAT5 signaling. Here, we show that in vitro IFN-β strongly suppressed GM-CSF production by T cells from healthy donors, untreated and IFN-β-treated MS patients, as well as patients diagnosed with other neurological diseases. IFN-β did not increase T cell apoptosis in our cell culture; hence, reduced production of GM-CSF by T cells was not due to pro-apoptotic effects of IFN-β. IFN-β significantly decreased the phosphorylation of STAT5 in total CD4+ T cells, including GM-CSF-producing CD4+ T cells. In summary, our findings suggest that IFN-β suppresses GM-CSF production by CD4+ T cells by inhibiting STAT5 signaling.