Immune Privilege and Eye-Derived T-Regulatory Cells

Abstract

Certain cellular components of the eye, such as neural retina, are unable to regenerate and replicate after destructive inflammation. Ocular immune privilege provides the eye with immune protection against intraocular inflammation in order to minimize the risk to vision integrity. The eye and immune system use strategies to maintain the ocular immune privilege by regulating the innate and adaptive immune response, which includes immunological ignorance, peripheral tolerance to eye-derived antigens, and intraocular immunosuppressive microenvironment. In this review, we summarize current knowledge regarding the molecular mechanism responsible for the development and maintenance of ocular immune privilege via regulatory T cells (Tregs), which are generated by the anterior chamber-associated immune deviation (ACAID), and ocular resident cells including corneal endothelial (CE) cells, ocular pigment epithelial (PE) cells, and aqueous humor. Furthermore, we examined the therapeutic potential of Tregs generated by RPE cells that express transforming growth factor beta (TGF-β), cytotoxic T lymphocyte-associated antigen-2 alpha (CTLA-2α), and retinoic acid for autoimmune uveoretinitis and evaluated a new strategy using human RPE-induced Tregs for clinical application in inflammatory ocular disease. We believe that a better understanding of the ocular immune privilege associated with Tregs might offer a new approach with regard to therapeutic interventions for ocular autoimmunity.

Figure 1

Molecular mechanism underlying the generation of regulatory T cells (Tregs) by murine iris pigment epithelial (PE) cells. Cultured iris PE cells suppress anti-CD3-driven T cell activation in vitro by direct cell contact in which B7-2 (CD86) expressed by iris PE cells interacts with cytotoxic T-lymphocyte antigen-4 (CTLA-4) on responding T cells. Furthermore, cultured iris PE cells expressing B7-2 induce the activation of CTLA-4⁺CD8⁺ T cells that express their own B7-2 and secrete enhanced amounts of active transforming growth factor beta (TGF-β), leading to the global suppression of entire T-cell populations including CD4⁺ T cells. Both iris PE cells and T cells exposed to iris PE cells upregulate their TGF-β and TGF-β receptor (TGF-βR) genes and suppress bystander T cells using membrane-bound or soluble TGF-β. In addition, iris PE cell-induced Foxp3⁺CD8⁺CD25⁺ Tregs suppress bystander T cells through cell contact via B7-2/CTLA-4 and/or programmed cell death- (PD-) 1/PD-L1 interactions. Thrombospondin-1 (TSP-1) produced from iris PE cells greatly contributes to the conversion of TGF-β from latent form to active form.

Figure 2

Molecular mechanism underlying the generation of regulatory T cells (Tregs) by murine retinal pigment epithelial (RPE) cells. RPE cells constitutively express cytotoxic T lymphocyte-associated antigen 2 alpha (CTLA-2α), a cathepsin L (CathL) inhibitor, which promotes the induction of Tregs. In addition, CD4⁺ T cells exposed to RPE cells predominantly express CD25 and Foxp3. CTLA-2α, thrombospondin-1 (TSP-1), and retinoic acid promote the development of CD4⁺CD25⁺ Foxp3⁺ Tregs by transforming growth factor beta (TGF-β) signaling in vitro. These Tregs produce high levels of TGF-β and suppress bystander T cells and experimental autoimmune uveoretinitis (EAU) induced by retinal antigen interphotoreceptor retinoid-binding protein (IRBP).

Figure 3

Regulatory T-cell (Treg) therapy in ocular disease: the original source of Tregs is the patient's peripheral blood. Following isolation of peripheral blood mononuclear cells (PBMCs) from the blood, PBMCs are cultured on anti-CD3-coated plates with RPE supernatants for 24 h. RPE supernatants are collected from culture media of human RPE cell lines with transforming growth factor beta 2 (TGF-β2) and high-dose interleukin 2 (IL-2). CD4⁺CD25⁺ T cells are first selected from cultured PBMCs. Sorted CD4⁺CD25⁺ T cells are then recultured with RPE supernatants together with recombinant IL-2 (rIL-2) and anti-CD3/CD28 antibodies for 72 h. In the final sort, CD4⁺CD25^highCD45RA⁻ T cells are collected, which are best suited for intravitreal injection into uveitis patients.