Desiccating Stress Induces CD4+ T-Cell Mediated Sjogren's Syndrome-Like Corneal Epithelial Apoptosis via Activation of the Extrinsic Apoptotic Pathway by Interferon-γ

We investigated the role of CD4(+) T-cell-produced interferon (IFN)-gamma on corneal epithelial apoptosis in a murine desiccating stress (DS) model that resembles Sjogren's syndrome. The DS model was generated in C57BL/6 (B6) and B6 IFN-gamma-knockout (B6 gamma KO) mice. Adoptive transfer of CD4+ T cells from DS-exposed donor to recombination activating gene (RAG)-1(-/-) recipient mice and topical neutralization of IFN-gamma were performed to determine whether IFN-gamma produced by pathogenic CD4(+) T cells promotes corneal epithelial apoptosis. Apoptosis in corneal epithelia was assessed by evaluating the expression and activity of caspases 3, 8, and 9. The activation of caspase-8 mediated increased corneal epithelial apoptosis in B6 mice after DS, and this was exacerbated by subconjunctival IFN-gamma injection. B6 gamma KO mice were resistant to DS-induced apoptosis; however, B6 gamma KO mice receiving IFN-gamma developed apoptosis similar to that observed in B6 wild-type mice. Adoptive transfer of CD4(+) T cells from donors subjected to DS increased corneal epithelial apoptosis via activation of caspase-8 in recipients, similar to that in the donor mice. Topical neutralization of IFN-gamma in adoptive transfer recipients decreased corneal epithelial apoptosis. DS, IFN-gamma administration, or CD4(+) T-cell adoptive transfer had no effect on the expression and activation of the intrinsic apoptosis mediator, caspase-9. CD4(+) T-cell-produced IFN-gamma plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway. (Am J Pathol 2011, 179:1807-1814; DOI: 10.1016/j.ajpath.2011.06.030)