Neuronal IFN-beta–induced PI3K/Akt-FoxA1 signalling is essential for generation of FoxA1(+)T(reg) cells

Neurons reprogramme encephalitogenic T cells (T(enc)) to regulatory T cells (T(regs)), either FoxP3(+)T(regs) or FoxA1(+)T(regs). We reported previously that neuronal ability to generate FoxA1(+)T(regs) was central to preventing neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Mice lacking interferon (IFN)-β were defective in generating FoxA1(+)T(regs) in the brain. Here we show that lack of neuronal IFNβ signalling is associated with the absence of programme death ligand-1 (PDL1), which prevents their ability to reprogramme T(enc) cells to FoxA1(+)T(regs). Passive transfer-EAE via IFNβ-competent T(enc) cells to mice lacking IFNβ and active induced-EAE in mice lacking its receptor, IFNAR, in the brain (Nes(Cre):Ifnar(fl/fl)) result in defective FoxA1(+)T(regs) generation and aggravated neuroinflammation. IFNβ activates neuronal PI3K/Akt signalling and Akt binds to transcription factor FoxA1 that translocates to the nucleus and induces PDL1. Conversely, inhibition of PI3K/Akt, FoxA1 and PDL1 blocked neuronal ability to generate FoxA1(+)T(regs). We characterize molecular factors central for neuronal ability to reprogramme pathogenic T cells to FoxA1(+)T(regs) preventing neuroinflammation.