CD4T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model.

Abstract

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, nerve damage-associated transcriptomic signature in the trigeminal ganglia, and sustained tear cytokine levels. Adoptive transfer of CD4T cells from WT DED mice to T cell-deficient mice reproduced corneal nerve damage but not epitheliopathy. Conversely, T cell-deficient mice reconstituted solely with naïve CD4T cells developed corneal nerve impairment and epitheliopathy upon DED induction, thus replicating the WT DED phenotype. Collectively, our data show that while corneal neuropathy is driven by CD4T cells in DED, corneal epithelial damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED.