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

作者：Liu Yawei; Marin Andrea; Ejlerskov Patrick; Rasmussen Louise Munk; Prinz Marco; Issazadeh Navikas Shohreh^*

来源：Nature Communications, 2017, 8(1): 14709.

DOI：10.1038/ncomms14709

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)-beta were defective in generating FoxA1(+)T(regs) in the brain. Here we show that lack of neuronal IFNb signalling is associated with the absence of programme death ligand-1 (PDL1), which prevents their ability to reprogramme Tenc cells to FoxA1(+)T(regs). Passive transfer-EAE via IFNb-competent Tenc cells to mice lacking IFNb and active induced-EAE in mice lacking its receptor, IFNAR, in the brain (NesCre: Ifnar(fl/fl)) result in defective FoxA1(+)T(regs) generation and aggravated neuroinflammation. IFNb 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.

• 出版日期2017-4-24