. 2018 Nov 5;119(10):1171–1181. doi: 10.1038/s41416-018-0258-8

Table 1.

Current understanding of the CNS immune system

Characteristic	Current understanding
Blood–brain barrier	Leukocyte entry into the CNS is mediated by adhesion signals on endothelial cells (ECs) of the BBB. Limited expression of adhesion signals on ECs in healthy CNS results in low immune surveillance.¹⁵⁷ In disease processes, infiltration of specific immune cell subsets is observed, which may be driven by BBB ECs or by immune cells within the CNS.¹⁵⁸ While naive T cell are absent within the CNS, activated T cells cross the BBB as patrolling memory T cells and regulatory T-cells; preventing inappropriate inflammation⁸ and facilitating myelin regeneration.¹⁵⁹
Lymphatic drainage	Extracellular fluid in the CNS is composed of cerebrospinal fluid (CSF) and interstitial fluid (ISF). CSF is mainly contained within the ventricular system and subarachnoid space, and drains directly into deep cervical and lumbar lymph nodes via lymphatic vessels associated with the nasal mucosa, dura mater and nerve roots.^{7, 160} ISF is found in the extracellular spaces of CNS parenchyma and drains into cervical lymph nodes via intramural perivascular drainage pathways in cerebral artery walls.^{7, 160} Both CSF and ISF may communicate within the brain parenchyma via the glial lymphatic system, a perivascular channel system formed by astroglial cells which removes waste proteins and macromolecules.^{161, 162} Tissue metabolites found within the glial lymphatic system traffic to deep cervical and lumbar lymph nodes via CSF. Within these lymph nodes, T cells may become primed and activated to recognise CNS-specific antigens.^{7, 156}
Antigen-presenting cells	Three subsets of dural macrophage populations have been identified, named for their location in the CNS.¹⁶³ Meningeal macrophages and choroid plexus macrophages are bone marrow derived, while perivascular macrophages appear to originate from haematopoietic stem cells in the embryonic yolk, an origin they share with microglial cells.⁷ These macrophage populations can all act as antigen-presenting cells. The position of perivascular macrophages allows them to sample both blood and CNS ISF, implying a possible role in communication between the CNS and periphery.¹⁶³ As well as this, there is evidence from in vivo models that brain parenchyma is completely screened every few hours by resting microglia.¹⁶⁴
Antigen presentation via MHC expression	CNS antigen presentation is thought to occur at the BBB by microglia, dural macrophages or dendritic cells at so-called CNS ‘immune gateways’ where MHC is expressed.¹⁵⁶ These gateways also act as entry ports for activated T cells, influx of which can be followed by monocyte recruitment that amplifies inflammatory reactions within CNS.¹⁵⁷