Immune Modulation of Macular Degeneration Through Natural Killer Cell Activity

Modelling retinal injury using a laser, we confirmed splenic NK cells were activated in response to distal retinal injury, with concordance between mouse and human lymphocytic activation patterns. scRNA-sequencing demonstrated expansion of a defined subset of activated cytolytic NK cells at the neovascular lesion site and found that NK cell proliferation, biogenesis and metabolic respiration is heightened during active resolution of retinal neovascular lesions.

We find that NK cells play a critical role in remodelling neovascular lesions through their cytotoxic activity, limiting pathology. We find NK cells localize to the basolateral side of neovessels in human AMD donor eye tissue and show that primary human retinal endothelial cells can act as target cells for NK cell-directed cytolysis. NK cells in both peripheral blood and donor eye tissue exhibit a variety of markers of NK cell quiescence in AMD and indicate NK cells have limited capacity for replenishment at the site of disease, which may be a factor in disease progression.

Adoptive NK cell immunotherapy with cytokine-activated NK cells reduces neovascular lesion volume and repairs neovessel barrier integrity in models of retinal neovascularization. Here, we propose that harnessing NK cells may represent a novel transformative therapeutic strategy for the prevention and treatment of neovascular eye disease.