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

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.H2(b) 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.