Neuronal IFN-beta–induced PI3K/Akt-FoxA1 signalling is essential for generation of FoxA1+Treg cells

Abstract

Abstract Neurons reprogramme encephalitogenic T cells (Tenc) to regulatory T cells (Tregs), either FoxP3+Tregs or FoxA1+Tregs. We reported previously that neuronal ability to generate FoxA1+Tregs was central to preventing neuroinflammation in experimental autoimmune encephalomyelitis (EAE). Mice lacking interferon (IFN)-β were defective in generating FoxA1+Tregs 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 Tenc cells to FoxA1+Tregs. Passive transfer-EAE via IFNβ-competent Tenc 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+Tregs 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+Tregs. We characterize molecular factors central for neuronal ability to reprogramme pathogenic T cells to FoxA1+Tregs preventing neuroinflammation.