Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells

Abstract

In both humans and animal models the development of Sjögren syndrome (SS) and non-SS keratoconjunctivitis sicca (KCS) increases with age. Here, we investigated the ocular surface and lacrimal gland phenotype of NOD.B10.H2b mice at 7–14, 45–50, and 96–100 weeks. Aged mice develop increased corneal permeability, CD4+ T cell infiltration and conjunctival goblet cell loss. Aged mice have lacrimal gland (LG) atrophy with increased lymphocyte infiltration and inflammatory cytokine levels. An increase in the frequency of CD4+Foxp3+ Tregs cells was observed with age in the cervical lymph node (CLN), spleen and LG. These CD4+CD25+ lose suppressive ability, while maintaining expression of Foxp3 and producing IL-17 and IFN-γ. An increase Foxp3+IL-17+ or Foxp3+IFN-γ+ was observed in the LG and LG-draining CLN. In adoptive transfer experiments, recipients of either purified Tregs or purified T effector cells from aged donors developed lacrimal keratoconjunctivitis, while recipients of young Tregs or young T effector cells failed to develop disease. Overall, these results suggest inflammatory cytokine-producing CD4+Foxp3+ cells participate in the pathogenesis of age-related ocular surface disease.

The Pathophysiology of Dry Eye Disease

“…161 Infiltration with autoreactive T cells and oxidative stress have also been observed in the aged lacrimal gland, indicating that aging is associated with inflammation and is not simply a degenerative process. 98, 137, 162–166 These studies suggest that similar to the ocular surface, a vicious cycle of inflammation and apoptosis involving infiltrating cells and glandular acinar cells perpetuates LG inflammation leading to glandular dysfunction in SS and age-related dry eye.…”

“…Indeed, dysfunctional Tregs that cannot suppress T effector activity, but produce IFN-γ and IL-17 have been observed in mouse models of dry eye induced by desiccating stress or associated with aging. 123, 137 Furthermore, adoptive transfer of either T effectors or Tregs from aged mice into naïve immunodeficient recipient mice caused goblet cell loss and lacrimal gland infiltration, while the adoptive transfer T effectors or Tregs from young mice did not, suggesting that age-related Treg dysfunction may contribute to induction of dry eye disease. 137 …”

“…138 The hallmarks of SS are lymphocytic infiltration of the lacrimal and salivary glands, serum autoantibodies, keratoconjunctivitis sicca and dry mouth. 139 Mouse models of SS and aging have identified a pathogenic role for CD4 + T 98, 137, 140–142 and B cells. 143–146 Mouse SS models that develop dacryoadenitis tend to be Th1 skewed 147–151 , whereas those that develop sialadenitis are Th17 skewed.…”

Review: The function of regulatory T cells at the ocular surface

“…This important finding implies that Tregs may demonstrate function-specific impairment with age – their ability to control immune activation against infection and tumors might be intact, yet they fail to suppress IL-17-driven autoimmunity [56]. Using NOD.B10.H2b mice, Coursey and colleagues showed that dacryoadenitis in aging is associated with a significant increase in Treg frequencies, despite worsened lacrimal gland pathology [57]. Furthermore, the investigators identified a population of Tregs that, despite continued expression of Foxp3, had impaired suppressive function and expressed the pro-inflammatory cytokines IL-17 and IFN-γ.…”

“…Furthermore, the investigators identified a population of Tregs that, despite continued expression of Foxp3, had impaired suppressive function and expressed the pro-inflammatory cytokines IL-17 and IFN-γ. The pathogenicity of these inflammatory cytokine-producing Tregs was confirmed in adoptive transfer experiments, in which recipients of either aged Tregs or aged effector T cells developed DED, whereas recipients of young Tregs or young effector T cells did not [57]. The plasticity of Tregs towards an effector cell phenotype may be an important factor contributing to the increased prevalence of DED with age.…”