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

Am J Pathol. 2011 Oct;179(4):1807-14. doi: 10.1016/j.ajpath.2011.06.030. Epub 2011 Aug 16.


We investigated the role of CD4(+) T-cell-produced 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-γ-knockout (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-cell-produced IFN-γ plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis* / drug effects
  • CD4-Positive T-Lymphocytes / pathology*
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Separation
  • Desiccation*
  • Epithelium, Corneal / drug effects
  • Epithelium, Corneal / enzymology
  • Epithelium, Corneal / pathology*
  • Female
  • In Situ Nick-End Labeling
  • Inflammation / pathology
  • Interferon-gamma / administration & dosage
  • Interferon-gamma / deficiency
  • Interferon-gamma / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutralization Tests
  • Signal Transduction / drug effects
  • Sjogren's Syndrome / immunology
  • Sjogren's Syndrome / pathology*
  • Stress, Physiological* / drug effects


  • Interferon-gamma
  • Caspases