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.