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

Abstract

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.