ReviewImmune regulation of the ocular surface
Introduction
The ocular surface consists of the corneal and conjunctival mucosal linings extending to the mucocutaneous junctions of the lid margins. The tear film - an aqueous medium enriched with lipids and mucins from meibomian glands and goblet cells, respectively, maintains the ocular interface with the external environment (Bron et al., 2017). The ocular surface is known as an "immune-privileged" site: It holds the capability to mount effective immune defense, but it employs tight regulatory measures to prevent unnecessary local inflammatory responses to preserve corneal integrity and function. In this review, we discuss the following regulatory mechanisms that are critical to maintaining immune homeostasis of the ocular surface: 1) Cornea avascularity: The cornea must stay transparent and, therefore, be avascular to function normally. The lack of blood vessels limits the ingress of circulating blood leukocytes, while lack of lymphatic vessels impedes leukocytes from migrating out of the tissue. Thus, corneal avascularity essentially contributes to the immune privilege of the cornea (Cursiefen, 2007). 2) The healthy cornea is devoid of 'mature’ leukocytes: The healthy cornea is devoid of lymphoid leukocytes but is endowed with a sizable number of myeloid leukocytes (Hamrah et al., 2002, 2003; Hattori et al., 2011, 2016; Yamagami et al., 2005, 2006), which function in both innate and adaptive immunity in response to external insults. These resident leukocytes are phenotypically "immature"; they express limited pro-inflammatory cytokines and are limited in their ability to sensitize lymphoid cells and provoke effector T cell responses. Rather, they promote induction of immune tolerance at the ocular surface (Hattori et al., 2016; Hamrah et al., 2002; Barabino et al., 2012; Lutz and Schuler, 2002). 3) Regulatory role of the corneal epithelium: The corneal epithelium prevents invasion of immunogenic molecules through its barrier function and actively contributes to immune quiescence regulation; this layer secretes various immunoregulatory factors that sustain the cornea's avascularity and preserve the "immature" status of resident leukocytes at the ocular surface (Shen et al., 2007; Griffith et al., 1995; Tan et al., 2018; Singh et al., 2020). 4) Neuroimmune cross-talk at the ocular surface: More recently, immunoregulatory function of corneal nerves and their cross-talk with immune cells has drawn significant interest. Indeed, the cornea is the most densely innervated tissue in the human body, and proper corneal innervation with the physiological levels of neuropeptides at the ocular surface has been demonstrated essential to promote immune homeostasis in addition to regulating tear secretion and the blink reflex (Yamada et al., 2002, 2003; Suvas, 2017). 5) Conjunctiva-associated lymphoid tissue (CALT) and goblet cells: Unlike the cornea, the conjunctiva harbors a diverse group of immune cells with dominant lymphoid cells (primarily T cells) during the steady-state conditions (Hingorani et al., 1997). Unique to the conjunctiva, some resident T cells aggregate in dense foci in a form of mucosa-associated lymphoid tissue (MALT) and are specifically termed conjunctiva-associated lymphoid tissue (CALT) (Knop and Knop, 2000). CALT increases in size and number after ocular antigen stimulation and is implicated in the induction of mucosal tolerance and protection from infectious and non-infectious insults (Siebelmann et al., 2013). In addition, a special type of epithelial cell within the conjunctiva is the goblet cell, which serves as the primary source for mucins that exert antimicrobial functions and induce tolerogenic dendritic cells (DC) (Gordon et al., 2005; Ko et al., 2018). 6) Regulatory T cells (Treg) in the regional lymph nodes: ‘Intraocular’ immune quiescence is primarily maintained through a phenomenon called anterior chamber-associated immune deviation (ACAID) that involves the spleen. However, the adaptive T cell immunity at the ‘ocular surface’ is mainly regulated within regional lymph nodes (Chauhan and Dana, 2009; Amouzegar et al., 2016). Indeed, suppression of effector T cells in the local lymphoid compartment is an essential mechanism maintaining the integrity of the ocular surface. In this regard, regulatory T cells (Treg) in the lymph nodes draining the ocular surface have been shown to potently suppress sensitization of naive T cells and function of activated T cells, thus preventing the loss of ocular surface immune quiescence (Chauhan and Dana, 2009; Amouzegar et al., 2016). Key cellular and molecular components participating in the immune regulation of the ocular surface are illustrated in Fig. 1.
Section snippets
Immunoregulatory function of corneal epithelium
The corneal epithelium is the frontline of innate ocular immunity. It forms a physical barrier against micro-organisms and environmental insults, maintained firmly by cellular structures including desmosomal junctions, hemidesmosomes, and basement membrane (Henriksson et al., 2009; Bergmanson, 2009). Additionally, there is increasing evidence demonstrating that the corneal epithelium has a critical immunoregulatory role in the eye. These cells constitutively express an array of immunoregulatory
Immunoregulatory function of corneal resident myeloid leukocytes
The normal cornea has no T or B lymphocytes but is endowed with bone marrow-derived principally myeloid immune cells characterized by a CD11b+CD3−CD19− phenotype, distributed predominantly at the periphery and decreasing gradually toward the center (Hamrah et al., 2002; Barabino et al., 2012). These resident myeloid cells comprise a major population of CD11b+CD11c− macrophages/monocytes in the deep stroma and CD11b+CD11c+ dendritic cells (DC) in the anterior stroma, along with a few CD11blo/−
Immunoregulatory function of corneal nerves and neuropeptides
The cornea is densely innervated by the ophthalmic branch of the trigeminal nerve, which enters the corneal stroma and further branches into the epithelium (Müller et al., 1996). The integrity of corneal nerves is essential for relaying the sensory signals and providing epithelial-trophic factors to maintain ocular surface homeostasis, including critical regulation of corneal epithelial cell and limbal stem cell survival (Dastjerdi and Dana, 2009; Ferrari et al., 2011; Ueno et al., 2012).
Immunoregulatory function of conjunctival goblet cells and CALT
Goblet cells are specialized epithelial cells in the conjunctiva serving as the primary source of mucins for tear film that covers the ocular surface (Floyd et al., 2012). Disrupted corneal barrier function is a major pathological feature in DED visualized by corneal fluorescein staining in the clinic, and decreased numbers and atrophy of conjunctival goblet cells have been consistently observed in DED (Chen et al., 2017; Fabiani et al., 2009; Ouyang et al., 2021). More recently, conjunctival
Immunoregulatory function of Treg
Regional eye-draining lymph nodes are the primary site where adaptive immunity is activated and regulated in ocular surface inflammation. Once the immature status of ocular surface resident APC is overridden by inflammatory stimulus, these APC become activated and mobilized, migrating to the local draining lymph nodes and priming naive CD4+ T cells through providing antigenic and co-stimulatory signals, as well as secreting T cell-polarizing cytokines (Kodati et al., 2014; Chen et al., 2011;
Conclusions and perspectives
The maintenance of ocular surface homeostasis by a variety of immunoregulatory mechanisms is critical to avoid excessive inflammation that may cause tissue damage and impairment of vision. Novel therapeutic strategies harnessing these critical mechanisms can be designed to enhance the immune regulation resulting in restoration of ocular surface homeostasis in a myriad of ocular surface diseases. In addition to the mainstay of the ocular surface-regional lymphoid compartment axis we have
Funding source
This work was supported by NIH grants EY20889 (RD) and EY012963 (RD) and NIH core grant P30EY003790.
Declaration of competing interest
R.D. is consultant to Novartis, GSK, and Kala and holds equity in Claris Biotherapeutics, Aramis Biosciences, GelMEDIX, and Kera Therapeutics. Massachusetts Eye and Ear owns intellectual property related to blockade of substance P in ocular immunoinflammatory diseases.
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