Desiccating stress induces CD4 + T-cell-mediated Sjögren's syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-γ

Xiaobo Zhang, Wei Chen, Cintia S. De Paiva, Eugene A. Volpe, Niral B. Gandhi, William J. Farley, De Quan Li, Jerry Y. Niederkorn, Michael E. Stern, Stephen C. Pflugfelder

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45 Scopus citations

Abstract

We investigated the role of CD4 + T-cellproduced interferon (IFN)-γ on corneal epithelial apoptosis in a murine desiccating stress (DS) model that resembles Sjögren's syndrome. The DS model was generated in C57BL/6 (B6) and B6 IFN-γknockout (B6γKO) mice. Adoptive transfer of CD4 + T cells from DS-exposed donor to recombination activating gene (RAG)-1 -/- recipient mice and topical neutralization of IFN-γ were performed to determine whether IFN-γ 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-γ injection. B6γKO mice were resistant to DS-induced apoptosis; however, B6γKO mice receiving IFN-γ 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-γ in adoptive transfer recipients decreased corneal epithelial apoptosis. DS, IFN-γ administration, or CD4 + T-cell adoptive transfer had no effect on the expression and activation of the intrinsic apoptosis mediator, caspase-9. CD4 + T-cellproduced IFN-γ plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway.

Original languageEnglish (US)
Pages (from-to)1807-1814
Number of pages8
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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