title: Desiccating stress induces CD4+ T-cell-mediated Sjögren's syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-γ.
abstract: 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.
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, and the Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Cintia S
authors.initials: CS
authors.lastname: De Paiva
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Volpe
authors.forename: Niral B
authors.initials: NB
authors.lastname: Gandhi
authors.forename: William J
authors.initials: WJ
authors.lastname: Farley
authors.forename: De-Quan
authors.initials: DQ
authors.lastname: Li
authors.forename: Jerry Y
authors.initials: JY
authors.lastname: Niederkorn
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stern
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation; D003890:Desiccation; D019573:Epithelium, Corneal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D005260:Female; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D015398:Signal Transduction / Q000187:drug effects; D012859:Sjogren's Syndrome / Q000276:immunology / Q000473:pathology*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D007371:Interferon-gamma; D020169:Caspases