Compartmentalized ocular lymphatic system mediates eye-brain immunity

The eye, an anatomical extension of the central nervous system (CNS), displays many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. In studying herpes virus immune responses in the brain, we observe an unexpected finding that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumors, allowing for therapeutic immune responses against glioblastoma via intravitreal immunization. Upon further interrogation, we show that the anterior and posterior compartments of the eye have two distinct lymphatic drainage systems, the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. Additionally, this posterior lymphatic drainage, like that of meningeal lymphatics, can be modulated with VEGF-C. Conversely, inhibition of lymphatic signaling on the optic nerve overcomes a major limitation in gene therapy, by diminishing immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and central nervous system diseases.