报告题目：Role of neurons in the regulation of auto-reactive T cells and central nervous system (CNS) inflammation
报 告 人：Yawei Liu, MD, PhD Associate Professor, Neuroinflammation BRIC, KU
We try to understand the molecular mechanisms of neuronal-T cell communication that is affecting transcriptional regulation of T cell differentiation and fate through modulation of epigenetic signatures, implicated in inflammatory diseases of the central nervous system/CNS. The research aim is to identify and characterize neuronal signaling pathways that conduct regulatory signals in the CNS-infiltrating T cells, affecting their transcriptional landscape, phenotype and their function in disease.
Previously we reported a novel function for neurons as being highly immune-competent cells, based on their crucial role in the regulation of T-cell responses and CNS inflammation in models of multiple sclerosis (Nature Medicine. 2006;12(5):518-525). The neuronal–T cell interactions result in switching pathogenic T cells to become regulatory T cells (Treg) with the capacity to suppress CNS inflammation. In a follow-up study, based on the fact that Ifnb-/- mice develop a higher degree of CNS inflammation and clinical symptoms of encephalomyelitis (EAE) than wild-type (WT) mice, We found a new T cell subset which is called FoxA1+Treg cells to have a suppressive function depending on the expression of high levels of PD-L1. Transferring of FoxA1+Tregs to Ifnb-/- mice suppressed the CNS pathology and progression of encephalomyelitis. Moreover, we found that FoxA1+Tregs are generated in relapsing-remitting multiple sclerosis patients that respond well to IFN-β treatment. (Nature Medicine. 2014 Mar;20(3):272-82).
In addition, I have also studied neuronal signaling and how neuronal signaling affect on FoxA1+Treg cells generation. We reported previously that neuronal ability to generate FoxA1+Tregs was central to preventing neuroinflammation in experimental autoimmune encephalomyelitis. Mice lacking the cytokine interferon (IFN) were defective in generating FoxA1+Tregs in the brain. Neuron-induced FoxA1+Tregs were capable of preventing chronic and demyelinating EAE in mice lacking IFN. Here we show that lack of neuronal IFN-signaling was associated with lack of neuronal expression of program death-ligand1 (PDL1), which also prevented their ability to reprogram encephalitogenic T cells to FoxA1+Tregs. Transfer of IFN competent encephalitogenic T cells to mice lacking IFN or its receptor; IFNAR in the brain (NesCre:Ifnarfl/fl) led to the absence of FoxA1+Tregs-generation and aggravated neuroinflammation. We identified that IFN activated neuronal PI3K/Akt signaling. Phosphorylated Akt consequently bound to transcription factor FoxA1, which upon translocation to the nucleus induced neuronal PDL1 expression. Conversely, inhibition of PI3K/Akt, or FoxA1 and PDL1 knock-down blocked neuronal ability to generate FoxA1+Tregs. Our study identified crucial molecular players central for neuronal ability to reprogram pathogenic T-cells and to generate FoxA1+Tregs, which could be a therapeutic target to prevent neuroinflammation. This manuscript is recently accepted by nature communication.