A dialog between regulatory T cells and microglia dictates white matter repair and long-term recovery aftertransient cerebral ischemia Ligen Shi, Qingxiu Zhang, Fei Xu, Angus W. Thomson, Jun Chen, Xiaoming Hu* Department of Neurology, University of Pittsburgh, Pittsburgh, USA We recently reported that CD4+CD25+ regulatory T cells (Tregs) exerted neuroprotection by targeting inflammatory dysregulation in acute stage of stroke. The long-term effect of Tregs on post-stroke brain repair, however, is not characterized. This study examined the roles of Tregs in stroke recovery and explored the mechanisms of protection in vivo in a 60-minute middle cerebral artery occlusion (tMCAO) model of ischemic stroke and in vitro using Treg-microglia co-cultures. A combined approach including cell-specific depletion, immunohistology staining, electron microscopy (EM), diffusion tensor imaging (DTI) and electrophysiology, was applied. Tregs were depleted by repeated injection of diphtheria toxin (DT) in transgenic DTR mice expressing the DT receptor under the control of the Foxp3 promoter. Treg deficiency resulted in deteriorated white matter damage 21d after stroke, which was rescued by post-stroke adoptive transfer of wild type Tregs. In contrast, expanding the number of Tregs in vivo using IL-2/IL-2-antibody complex (IL2/IL2Ab, ip) promoted structural and functional integrity of white matter, as revealed by immunohistology staining, EM, DTI and electrophysiology. The enhanced white matter integrity in IL2/IL2Ab-treated stroke mice was associated with improved neurological functions lasting out to 35d after stroke. Mechanistic studies revealed a potent effect of Tregs in promoting oligodendrocyte precursor cell (OPC) differentiation in the ischemic brain and in Treg-mixed glia co-cultures. Interestingly, Treg-afforded oligodendrogenesis was immensely attenuated in microglia depleted (with PLX5662) mice, but not in lymphocyte deficient Rag1 -/- mice. In vitro study confirmed that Tregs enhanced the expression of anti-inflammatory and tissue repairing genes in microglia. The absence of microglia in the co-culture system significantly reduced the capacity of Tregs to promote OPC differentiation. In conclusion,Treg-microglia interaction confers a healthy microglia response and provides a permissive environment for oligodendrogenesis. Boosting Treg responses represents a potential therapeutic strategy to enhance white matter repair and promote long-term recovery after stroke.
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