NFAT specific inhibition in T cells ameliorates experimental autoimmune encephalomyelitis by regulation of Th1 and Th17 cell differentiation

Abstract

Nuclear factor of activated T cells (NFAT) is an important transcription factor for T-cell activation and proliferation. Recently, NFAT has been more highlighted to control specific gene expressions in differentiation of CD4 T helper subsets including T helper 1 (Th1), Th2, Th17, regulatory T (Treg), and follicular helper T cells (Tfh). Therefore, regulation of NFAT role could be an important strategy to change T cell fate and applying for autoimmune diseases. To modulate NFAT function in T cells, we utilized NFAT inhibitory peptide, VIVIT conjugated with a cell penetrating peptide dNP2, which could across through blood-brain barrier. NFAT inhibition by dNP2-VIVIT peptide treatment in mouse naïve CD4 T cells showed significant inhibitory effects on T cell differentiation into Th1 and Th17 cells without affecting regulatory T cells, whereas Cyclosporine A inhibits regulatory T cell differentiation as well as Th1 and Th17 cells. Next, we proved that dNP2- VIVIT treatment to experimental autoimmune encephalomyelitis (EAE) mice reduced disease severity and demyelination with decreased CNS-infiltrating IFN-γ and IL-17 producing CD4+ T cells with comparable amount of Foxp3 expressing cells. Moreover, dNP2-VIVIT treatment to NP-OVA immunized mice showed decreased CXCR5+Bcl6+ Tfh cells. Collectively, these results suggest that NFAT specific inhibition by VIVIT peptide delivery in T cells could be a T cell modulatory drug for autoimmune diseases like multiple sclerosis.