**Abstract**

The eye is a delicate organ that, along with other tissues such as the testicles and brain, is considered immune-privileged. Immune cells that reside in the eye must create a tolerogenic microenvironment to prevent unwanted aggressive inflammatory reactions that can compromise function. However, the eye is exposed to persistent environmental insult that may overwhelm immune tolerance and result in eye diseases from diverse origins (autoimmune, infectious, and inflammatory). The immune system plays a central role in the different phases of eye diseases, as alterations in immune cells in response to mechanical, chemical, or infectious stimuli initiate and amplify the immune response that lead to ocular tissue damage. Both resident and infiltrating immune cells also actively inhibit the immune response and promote tissue repair. Emerging evidence is leading to a better understanding of how and when lymphocytes, amongst other immune cells, contribute to inflammatory diseases such as dry eye disease (DED). We have compiled literature identifying the presence and participation of lymphocyte subpopulations that modulate DED from studies in both mice and humans. Notably, most mouse studies have relied on desiccant-stress-induced models (non-autoimmune DED), whereas human studies are predominantly in patients with Sjögren's syndrome (autoimmune DED).

**Keywords:** Dry eye disease, Lymphocytes, Inflammation, Ocular surface, Ocular therapy

#### **1. Introduction**

As a part of the central nervous system (CNS) and as an organ constantly exposed to a wide range of environmental stimuli, the eye has finely regulated immune-defense mechanisms. The eye can simultaneously respond to invading pathogens and tolerate beneficial, resident bacterial communities (ocular microbiota) while conducting its vital function, to capture luminous stimuli and transfer the signal to the brain so that they can be assimilated, and images are ultimately interpreted [1]. This finely tuned ocular function is protected by immune tolerance and defense mechanisms that are highly coordinated [2].

Physical barriers such as the blood–brain barrier (BBB) and the blood–retina barrier (BRB) prevent infiltration of systemic blood antigens into the eye protecting against a potential immune trigger [1]. Innate and adaptive immune cell populations are strategically positioned both dispersed throughout the ocular tissue and in organized follicles along the eye tissues (eye-associated lymphoid tissue (EALT)) [3]. This actively promotes a tolerogenic microenvironment, which is maintained by

specific programs displayed by these immune cells. For example, antigen-presenting cells (APCs) express low levels of MHCII and costimulatory molecules (CD80 and CD86), and resident T cells show low production of interferon gamma (IFNγ) and enhanced transforming growth factor (TGF) β and interleukin 10 (IL-10). An additional, highly efficient eye component is tear production by the lacrimal gland. Tears are complex fluids whose role is to lubricate the ocular surface by binding to the epithelial surface via the inner mucin layer and to cooperate in microbial containment (both pathogen and commensals) as tears contain antimicrobial peptides (AMPs) such as lysozyme, lipocalin, lactoferrin, and immunoglobulin A (IgA), which inhibit microbial adherence [4–6]. Therefore, diverse surveillance pathways collaborate in a coordinated fashion to maintain eye homeostasis.

Despite the effort displayed by the above-mentioned tolerance and defense mechanisms, the eye faces challenging situations where overwhelming or persistent insults may ultimately alter homeostasis resulting in ocular pathologies. Eye disease can arise from the complex interaction between host (genetics, immunity, age, and sex) and the environment (air pollution, device exposure, and unsupervised medication). Multifactorial origins ranging from infectious and inflammatory to autoimmune can result in complex, yet unrelated co-morbidities.

#### **1.1 Dry eye disease**

Ocular surface inflammatory diseases such as dry eye disease (DED), which is currently the most frequent reason for ophthalmologic visits is projected to be an increasing eye morbidity due to lifestyle changes such as prolonged device use [7, 8]. DED is a group of diseases characterized by a strong inflammatory response targeting the ocular surface (conjunctiva, cornea, and meibomian and lacrimal glands) [7]. The most updated classification subdivides DED into two broad types: tear-deficient (aquodeficient) and evaporative DED. In the aquodeficient DED subtype, malfunctioning lacrimal glands (LGs) are often diagnosed. Deficiency in LG function is strongly associated with an autoimmune response targeting the body's salivary and lacrimal glands (Sjögren's syndrome) [7]. In evaporative DED, a reduced or altered lipidic composition of tear film is thought to be responsible [8]. Meibomian gland dysfunction (MGD) can result in decreased lipidic production, which is associated with infectious (bacterial and parasite) and non-infectious (hormones and duct obstruction) processes [7].

Manifestations compatible with those observed in DED are widely reported worldwide, positioning DED as the most common eye disease. DED is the most common eye pathology because this disease can emerge as a primary phenotype; that is, a local immune response is generated and sustained in the ocular surface and draining lymph nodes [9]. DED is also found as a secondary phenotype, where both autoinflammatory (e.g., colitis) [10, 11] and autoimmune diseases (Sjögren's syndrome, rheumatoid arthritis, and lupus) present DED symptoms [12–14]. The relevant finding that DED onset precedes autoimmune and non-autoimmune diseases in several patients is puzzling, and it has attracted interest from researchers worldwide, but the pathways remain to be elucidated.

Regardless of the origin, immune cells and their secreted products are the driving force of DED [9, 15]; therefore, a comprehensive understanding of the immune response as an initiator and perpetuating factor in DED is an area of intense research. Our immune system is composed of organs, cells, and molecules performing in a highly coordinated fashion; although finetuned mechanisms of regulation exist, pathologies prove that these mechanisms are not always limiting the intensity of the immune response. From the many cellular components of the immune response participating in DED, lymphocytes constitute one important component,

which, when danger signals are detected, can be activated and become a diseasepromoting player rather than homeostasis-maintaining cell type.
