Choroidal neovascularization (CNV) is directly related to visual loss in age-related macular degeneration and other macular disorders. We have investigated the role of CD1d-restricted invariant natural killer T (NKT) cells in laser-induced experimental CNV. Quantitative real-time PCR detected increased expression of NKT cell-related genes (Va14 and CXCL16) in whole eyes undergoing CNV, indicating local accumulation of NKT cells. We found a significant reduction of CNV and lower concentrations of vascular endothelial growth factor (VEGF) in ocular fluid in two different NKT cell-deficient mice, CD1d knockout (KO) and J alpha 18 KO mice. We also established in vitro co-cultures of retinal pigment epithelial cells and splenic NKT cells, and confirmed NKT cells could produce VEGF in the dish. Moreover, inoculating a-galactosylceramide, the ligand for NKT cells, into the vitreous cavity of C57BL/6 mice promoted CNV. We concluded that NKT cells play an important role in CNV as an inducer of VEGF. (C) 2008 Elsevier Inc. All right reserved.