Immune regulation of the ocular surface

Abstract

Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.

Keywords: Alloimmunity; Autoimmunity; Immune regulation; Inflammation; Ocular surface.

Figure 1.. The major cells and molecules promoting ocular surface immune homeostasis.

(1) Cornea: Epithelium constitutively expresses an array of immunoregulatory factors to suppress inflammatory cells and inhibit angiogenesis, including membrane-bound programmed death ligand-1 (PD-L1), Fas ligand (FasL), and vascular endothelial growth factor receptor-3 (VEGFR-3), as well as secreted pigment epithelial-derived factor (PEDF), thrombospondin-1 (TSP-1), soluble VEGFR-1 (sVEFGR-1), and IL-10. The tolerogenic antigen-presenting cells (APC) and plasmacytoid dendritic cells (DC) primarily residing in the stroma are critically involved in the induction of immune tolerance at both ocular surface and regional lymph nodes, and plasmacytoid DC additionally contribute to corneal nerve integrity and avascularity. The intense innervation of the cornea is essential for ocular surface barrier function and epithelial health with the support from the physiological level of substance P (SP) expressed by the nerves (¹Excessive SP, on the contrary, promotes ocular surface inflammation and tissue damage). Other cornea nerve-derived neuropeptides, including vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) exert important anti-inflammatory functions. (2) Conjunctiva: The specialized goblet cells in the epithelium are critical to maintaining tear film stability by secreting soluble mucins. It promotes ocular surface immune tolerance by inducing tolerogenic APC. In addition, conjunctiva-associated lymphoid tissue (CALT), which harbors regulatory T cells (Treg) is involved in the protective mucosal immune regulation. (3) Regional lymph nodes: Ocular surface adaptive immunity is primarily regulated in the local eye-draining lymph nodes by the specialized immunoregulatory cells – Treg, which include the larger thymus-derived Treg (tTreg) population and the smaller but more potent peripheral induced Treg (pTreg) population after antigen stimulation by tolerogenic APC or plasmacytoid DC.