Autoimmunity in Dry Eye Is Due to Resistance of Th17 to Treg Suppression

Abstract

Dry eye disease (DED), an inflammatory autoimmune disorder affecting the ocular surface, degrades visual performance and the quality of life of >10 million people in the United States alone. The primary limitation in the effective treatment of DED is an incomplete understanding of its specific cellular and molecular pathogenic elements. Using a validated mouse model of DED, herein we functionally characterize the different T cell subsets, including regulatory T cells (Tregs) and pathogenic effector T cells, and determine their contribution to the pathogenesis of DED. Our data demonstrate the presence of dysfunctional Tregs and the resistance of pathogenic T cells, particularly Th17 cells, to Treg suppression in DED. In addition, we clearly show that in vivo blockade of IL-17 significantly reduces the severity and progression of disease, which is paralleled by a reduction in the expansion of Th17 cells and restoration of Treg function. Our findings elucidate involvement of a previously unknown pathogenic T cell subset (Th17) in DED that is associated specifically with Treg dysfunction and disease pathogenesis and suggest a new target for dry eye therapy.

Interleukin-17-Mediated Control of Parasitemia in ExperimentalTrypanosoma congolenseInfection in Mice

“…To determine whether IL-17 plays a role in the pathogenesis of experimental T. congolense infection, we treated infected C57BL/6 mice with anti-IL-17 antibody to neutralize IL-17 activity and monitored the parasitemia levels. The dose and regimen of antibody treatment used here has been shown to effectively neutralize IL-17 activity in vivo in different experimental models (4,8,31). Surprisingly, anti-IL-17 antibody-treated mice had higher peak parasitemia throughout the infection period.…”

Spontaneous Autoimmune Dacryoadenitis in Aged CD25KO Mice

“…25 Additional studies in experimental murine dry eye have reported an IL-17A-mediated dysfunction of regulatory T cells, with a reduction of Th-17 cell expansion and restoration of Treg function after in vivo blockade of IL-17A. 43 An additional Th-17-associated cytokine, IL-21, was found to have increased mRNA expression in CD25KO compared with wild-type LG, with a significant time-related decrease. An emerging role for IL-21 in autoimmunity is supported by observations of elevated levels of the cytokine and its receptor in the sera of patients with SS, rheumatoid arthritis, systemic sclerosis, and inflammatory bowel disease.…”

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

“…In this context, it is of note that the recent studies suggest that autoreactive memory CD4 1 T lymphocytes induced during acute uveitis can mediate a chronic form of the disease [29]. It is also important to note that autoimmunity in Dry Eye Disease has recently been shown to due to the resistance of Th17 to Treg suppression [30]. Although the exact mechanism underlying Treg-mediated suppression of CD4 1 effector T cells is unknown, it is thought to derive in part from the prodigious consumption of IL-2 by Treg cells, resulting in the depletion of IL-2 required for expansion of CD4 1 CD25 À effector T cells.…”