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Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the  outer walls  of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the  castle moat , namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the  castle moat  is bordered by a second  wall , the  glia limitans , composed of astrocytic foot processes and a parenchymal basement membrane. Inside the  castle , that is the CNS parenchyma proper, the  royal family  of sensitive neurons resides with their  servants , the glial cells. Within the CSF-drained  castle moat , macrophages serve as guards collecting all the information from within the  castle , which they can present to the immune-surveying T cells. If in their communication with the  castle moat  macrophages, T cells recognize their specific antigen and see that the  royal family is  in danger, they will become activated and by opening  doors in the outer wall of the castle  allow the entry of additional immune cells into the  castle moat . From there, immune cells may breach the inner  castle wall  with the aim to defend the  castle inhabitants  by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the  castle inhabitants , this may allow for continuous entry of immune cells into the  castle  and lead to the death of the  castle inhabitants , and finally members of the  royal family , the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner  walls  of the CNS  castle moat  and will highlight the importance of the CSF-drained  castle moat  in maintaining immune surveillance and in mounting immune responses in the CNS.

Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle