Compartmentalized ocular lymphatic system mediates eye–brain immunity

Xiangyun Yin, Sophia Zhang, Ju Hyun Lee, Huiping Dong, George Mourgkos, Gordon Terwilliger, Aurora Kraus, Luiz Henrique Geraldo, Mathilde Poulet, Suzanne Fischer, Ting Zhou, Farrah Shalima Mohammed, Jiangbing Zhou, Yongfu Wang, Seth Malloy, Nicolas Rohner, Lokesh Sharma, Irene Salinas, Anne Eichmann, Jean-Leon Thomas, W. Mark Saltzman, Anita Huttner, Caroline Zeiss, Aaron Ring, Akiko Iwasaki and Eric Song ()
Additional contact information
Xiangyun Yin: Yale School of Medicine
Sophia Zhang: Yale School of Medicine
Ju Hyun Lee: Yale School of Engineering and Applied Science
Huiping Dong: Yale School of Medicine
George Mourgkos: Yale School of Medicine
Gordon Terwilliger: Yale School of Medicine
Aurora Kraus: University of New Mexico
Luiz Henrique Geraldo: Yale School of Medicine
Mathilde Poulet: Yale School of Medicine
Suzanne Fischer: Yale School of Medicine
Ting Zhou: Yale School of Medicine
Farrah Shalima Mohammed: Yale School of Engineering and Applied Science
Jiangbing Zhou: Yale School of Engineering and Applied Science
Yongfu Wang: Stowers Institute for Medical Research
Seth Malloy: Stowers Institute for Medical Research
Nicolas Rohner: Stowers Institute for Medical Research
Lokesh Sharma: Yale School of Medicine
Irene Salinas: University of New Mexico
Anne Eichmann: Yale School of Medicine
Jean-Leon Thomas: Yale School of Medicine
W. Mark Saltzman: Yale School of Engineering and Applied Science
Anita Huttner: Yale School of Medicine
Caroline Zeiss: Yale School of Medicine
Aaron Ring: Yale School of Medicine
Akiko Iwasaki: Yale School of Medicine
Eric Song: Yale School of Medicine

Nature, 2024, vol. 628, issue 8006, 204-211

Abstract: Abstract The eye, an anatomical extension of the central nervous system (CNS), exhibits 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. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the 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 CNS diseases.

Date: 2024
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DOI: 10.1038/s41586-024-07130-8

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