CNS Repair Requires Both Effector and Regulatory T Cells with Distinct Temporal and Spatial Profiles

Monocyte-derived macrophages (mo-M Phi s) and T cells have been shown to contribute to spinal cord repair. Recently, the remote brain choroid plexus epithelium (CP) was identified as a portal for monocyte recruitment, and its activation for leukocyte trafficking was found to be IFN-gamma-dependent. Here, we addressed how the need for effector T cells can be reconciled with the role of inflammation-resolving immunecells in the repair process. Using an acute spinal cord injury model, we show that in mice deficient in IFN-gamma-producing Tcells, the CP was not activated, and recruitment of inflammation-resolving mo-M Phi to the spinal cord parenchyma was limited. We further demonstrate that mo-M Phi locally regulated recruitment of thymic-derived Foxp3(+) regulatory T (Treg) cells to the injured spinal cord parenchyma at the subacute/chronic phase. Importantly, an ablation protocol that resulted in reduced Tregs at this stage interfered with tissue remodeling, in contrast to Treg transient ablation, restricted to the 4 d period before the injury, which favored repair. The enhanced functional recovery observed following such a controlled decrease of Tregs suggests that reduced systemic immunosuppression at the time of the insult can enhance CNS repair. Overall, our data highlight a dynamic immune cell network needed for repair, acting in discrete compartments and stages, and involving effector and regulatory T cells, interconnected by mo-M Phi. Any of these populations may be detrimental to the repair process if their level or activity become dysregulated. Accordingly, therapeutic interventions must be both temporally and spatially controlled.