Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance

Abstract

At steady state, the CNS parenchyma has few to no lymphocytes and less potent Ag-presentation capability compared with other organs. However, the meninges surrounding the CNS host diverse populations of immune cells that influence how CNS-related immune responses develop. Interstitial and cerebrospinal fluid produced in the CNS is continuously drained, and recent advances have emphasized that this process is largely taking place through the lymphatic system. To what extent this fluid process mobilizes CNS-derived Ags toward meningeal immune cells and subsequently the peripheral immune system through the lymphatic vessel network is a question of significant clinical importance for autoimmunity, tumor immunology, and infectious disease. Recent advances in understanding the role of meningeal lymphatics as a communicator between the brain and peripheral immunity are discussed in this review.

Figure 1.

Routes of fluid and solute passage through the brain. Fluid continuously enters the CNS from blood either (a) directly to interstitial fluid at the cerebrovasculature or (b) as cerebrospinal fluid via secretion at the choroid plexus. Fluid exits to lymph through (c) meningeal lymphatic vessels or (d) directly back to the blood at the dural venous sinuses. This movement mobilizes solutes including CNS antigen as well as cytokines towards the immune cell populations of the meninges. The cervical lymph nodes (e) can receive solutes either in lymph or in draining meningeal APCs for sampling and processing. Ultimately, these routes all reconvene in the blood, which is in turn subject to immune surveillance by the spleen and liver.