TY - JOUR
T1 - Neuronal IFN-beta-induced PI3K/Akt-FoxA1 signalling is essential for generation of FoxA1(+)Treg cells
AU - Liu, Yawei
AU - Marin, Andrea
AU - Ejlerskov, Patrick
AU - Rasmussen, Louise Munk
AU - Prinz, Marco
AU - Issazadeh-Navikas, Shohreh
PY - 2017/4/24
Y1 - 2017/4/24
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms14709
DO - 10.1038/ncomms14709
M3 - Journal article
C2 - 28436428
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 14709
ER -