Glymphatics and meningeal lymphatics unlock the brain-immune code.

The central nervous system (CNS) was once perceived as entirely shielded from the immune system, protected behind the blood-brain barrier and thought to lack lymphatic drainage. However, recent evidence has challenged many dogmas in neuroimmunology. Indeed, by means of glymphatics, brain-derived "waste" from deep within the CNS mobilizes toward immunologically active brain borders, where meningeal lymphatic vessels are appropriately positioned to drain antigens from the brain to the periphery. Accordingly, the presentation of brain-derived self-peptides emerges at the brain's borders and drives T cell responses with suppressive properties, critical in allowing active immunosurveillance while limiting aberrant immune reactivity. Taking into consideration these concepts, we further discuss how inflammation, aging, and neurodegenerative diseases potentially reshape the repertoire of self-antigens and immune cells, disrupting the healthy dialogue between the CNS and immune system. Collectively, this evolving perspective unveils new therapeutic avenues for CNS pathologies.