The central nervous system undergoes constant immune surveillance, but the route that immune cells take to exit the brain has been unclear as it had been thought to lack a classical lymphatic drainage system; here functional lymphatic vessels able to carry both fluid and immune cells from the cerebrospinal fluid are shown to be located in the brain meninges. The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system. Jonathan Kipnis and colleagues now show that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders. One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment1,2,3, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood4,5,6. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

The recent (re)discovery of the meningeal lymphatic system has opened new theories as to how immune cells traffic and interact with the central nervous system (CNS). While evidence is accumulating on the contribution of the meningeal lymphatic system in both homeostatic and disease conditions, a lot remains unknown about the mechanisms that allow for interaction between the meningeal lymphatic system and immune cells. In this review, we synthesize the knowledge about the lymphatic immune interaction in the CNS and highlight the important questions that remain to be answered.

Although macrophages in the meningeal compartments of the central nervous system (CNS) have been comprehensively characterized under steady state, studying their contribution to physiological and pathological processes has been hindered by the lack of specific targeting tools in vivo. Recent findings have shown that the dural sinus and its adjacent lymphatic vessels act as a neuroimmune interface. However, the cellular and functional heterogeneity of extrasinusoidal dural macrophages outside this immune hub is not fully understood. Therefore, we comprehensively characterized these cells using single-cell transcriptomics, fate mapping, confocal imaging, clonal analysis, and transgenic mouse lines. Extrasinusoidal dural macrophages were distinct from leptomeningeal and CNS parenchymal macrophages in terms of their origin, expansion kinetics, and transcriptional profiles. During autoimmune neuroinflammation, extrasinusoidal dural macrophages performed efferocytosis of apoptotic granulocytes. Our results highlight a previously unappreciated myeloid cell diversity and provide insights into the brain’s innate immune system.