CD4+ T cells drive corneal nerve damage but are dispensable for corneal epitheliopathy development in dry eye disease

Abstract

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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/586336v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1138e85org.highwire.dtl.DTLVardef@f1d0c7org.highwire.dtl.DTLVardef@1c1cccaorg.highwire.dtl.DTLVardef@6c09a7_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementDry 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.