CD4+T cells drive corneal nerve damage but not epitheliopathy in an acute aqueous-deficient dry eye model

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the cornea epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4 + T 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 CD4 + T 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 naive CD4 + T 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 CD4 + T cells in DED, corneal epithelia damage develops independently of the adaptive immune response. These findings have implications for T cell-targeting therapies currently in use for DED. Graphical abstract Significance Statement Dry eye is a frequent ocular disorder in which damage to the corneal epithelium and nerves is triggered by inadequate lubrication. The local CD4 + T cell-predominant immune response aggravates ocular surface impairment but the exact contribution of these cells to corneal epithelial and neural disease remains undetermined. Using adoptive transfer of T cells into T cell-deficient mice, trigeminal transcriptomics, and tear cytokine analysis, we delineate the pathogenic role of CD4 + T cells, revealing that they drive corneal nerve damage but are dispensable for epithelial disease to develop in response to desiccation. CD4 + T cells promote corneal neuropathy possibly by releasing proinflammatory cytokines onto the ocular surface. These findings have implications for T cell-targeting therapies currently used for dry eye.