JAK2 is overexpressed in human multiple sclerosis Th17 cells and stabilizes cell surface expression of IFN-γR2 (114.14)

Abstract

Abstract IFN-β inhibits the expansion of T helper 17 (Th17) cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. Here we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells from patients with AMS compared with those with inactive MS (IMS) or healthy subjects (HS). Anti-CD3 mAb stimulation and IFN-γ decreased the frequency of Th17 cells in peripheral blood mononuclear cells (PBMC) from AMS patients. Stimulation of PBMC from HS in Th17-polarizing conditions resulted in enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in MS and possibly other inflammatory diseases.