NFAT-Specific Inhibition by dNP2-VIVIT Ameliorates Autoimmune Encephalomyelitis by Regulation of Th1 and Th17

Abstract

Nuclear factor of activated T cells (NFATs) is an important transcription factor for T cell activation and proliferation. Recent studies have highlighted the role of NFATs in regulating the differentiation of effector CD4 T helper (Th) subsets including Th1 and Th17 cells. Because controlling the effector T cell function is important for the treatment of autoimmune diseases, regulation of NFAT functions in T cells would be an important strategy to control the pathogenesis of autoimmune diseases. Here, we demonstrated that an NFAT inhibitory peptide, VIVIT conjugated to dNP2 (dNP2-VIVIT), a bloodbrain barrier-permeable peptide, ameliorated experimental autoimmune encephalomyelitis (EAE) by inhibiting Th 1 and Th17 cells, but not regulatory T (T-reg) cells. dNP2-VIVIT negatively regulated spinal cord-infiltrating interleukin-17A (IL17A) and interferon (IFN)-gamma-producing CD4(+ )T cells without affecting the number of Foxp3(+) CD4(+) T reg cells, whereas dNP2-VEET or 11R-VIVIT could not significantly inhibit EAE. In comparison with cyclosporin A (CsA), dNP2-VIVIT selectively inhibited Thl and Th17 differentiation, whereas CsA inhibited the differentiation of all T cell subsets including that of Th2 and T reg cells. Collectively, this study demonstrated the role of dNP2-VIVIT as a novel agent for the treatment of autoimmune diseases such as multiple sclerosis by regulating the functions of Th1 and Th17 cells.