Immunological homeostasis of the eye

Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses. Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4(+) T cells, Th1 and Th17 cells, play an effector role in ocular inflammation. The eye has a unique regional immune system to protect vision-related cells and tissues from these effector T cells. The immunological balance between the pathogenic CD4(+) T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and production of inflammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-to-cell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25(+)Foxp3(+) Treg cells that also suppress the activation of bystander T cells. Iris PE cells convert CD8(+) T cells into Treg cells, while retinal PE cells convert CD4(+) T cells greatly and CD8(+) T cells moderately into Treg cells. CE cells also convert both CD4(+) T cells and CD8(+) T cells into Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membrane-bound molecules that include TGF-β TSP-1, B7-2 (CD86), CTLA-2α, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar immune properties to induce Treg cells. Although there are many issues to be answered, human Treg cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules can be applied as immune therapy for refractive autoimmune uveitis in humans in the future.