The barrier function of the retinal pigment epithelium (RPE) secures a highly selective exchange of molecules between the blood stream of the choroid and retina but also maintenance of the immune privilege of the retina. The latter function includes a mechanical barrier through the tight junctions and immune barrier of either membrane bound or secreted immune-suppressive factors in response to increasing inflammatory activities in the outer retina. However, in disease, both physical and immune barriers are compromised to allow accumulation of immune cells in the subretinal space or even to pass across the RPE into the retinal space. The ability of the RPE to secrete immune stimulatory factors such as MCP-1, as a response to the increased inflammation, suggests that disease goes along with an immunogenic switch. We recently found that stressed RPE cells express the transcription factor FoxP3 and its activation leads to secretion of pro-inflammatory factors. Indeed, RPE cells in either mouse models with age-related macular degeneration (AMD) relevance or in retinas from AMD patients, express FoxP3 in the RPE, which was not observed in healthy donors. FoxP3 appears first as a rescue factor for the RPE in the increasing presence of pro-inflammatory proteins such as IL1β or active complement that eventually changes the immunogenic phenotype from anti-inflammatory to pro-inflammatory.