In Human Multiple sclerosis, T helper 17 lymphocytes display increased levels of JAK2 that stabilize cell surface IFN-YR2chain

The refractoriness of T cells to the inhibitory effect of Interferon (IFN)-g is mainly attributed to down-regulation of IFN-gR2 signalling chain. Here we show that IFN-gR2 accumulated on the cell surface of in vitro generated Th17 cells, as opposed to Th1 cells, and rendered them sensitive to IFN-g/STAT1 signaling. Of note, a more pronounced IFN-gR2 cell surface expression and sensitivity to IFN-g was observed in peripheral Th17 cells from multiple sclerosis patients than in Th17 from healthy subjects. Analysis of IFN-gR2 mRNA and protein in T cell clones from multiple sclerosis patients and polarized T cells from healthy subjects showed that IFN-gR2 was equally expressed in Th1 and Th17 cells, whereas mRNA for JAK2 was highly expressed in Th17 cells only. JAK2-deficient g2A cells displayed a rapid internalization and degradation of cell surface IFN-gR2, which was prevented by transduction of JAK2. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-gR2 surface expression in self-reactive Th17 cells and renders them sensitive to IFN-g.