Purchase this article with an account.
Jun Chen, Reiko Horai, Phyllis B. Silver, Chi-Chao Chan, Rachel R. Caspi; Deficiency of IFN-gamma Delays the Onset of Spontaneous Uveitis in IRBP T cell Receptor Transgenic Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2947.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Our previous studies revealed the dual effect of IFN-γ in experimental autoimmune uveitis (EAU). IFN-γ is protective in EAU induced by immunization with IRBP. Conversely, however, IFN-γ is required for disease induction in EAU induced by IRBP-pulsed dendritic cells, and adoptively transferred polarized Th1 cells (IFN-γ-producing) are highly pathogenic. To investigate the role of IFN-γ in the pathogenesis of uveitis, we used a newly developed spontaneous EAU model in IRBP T cell receptor transgenic (TCR Tg) mice crossed onto an IFN-γ knockout background (GKO).
IRBP TCR Tg mice were generated on the EAU-susceptible B10.RIII background. GKO mice were backcrossed onto the B10.RIII background, and then crossed to IRBP TCR Tg mice (Tg-GKO). IRBP-specific T cells were detected using IRBP161-180/I-Ar/IgG1 dimers. Disease was evaluated by fundoscopy and histology. Lymphocyte proliferation was measured by [3H]-Thymidine incorporation. Cytokine levels were determined by ELISA or by flow cytometry with intracellular staining.
Lymphocytes of Tg-GKO mice contained similar frequency of IRBP-specific T cells, as judged by antigen-specific dimer reagent, and showed comparable proliferative responses to IRBP peptide to their IFN-γ-sufficient TCR Tg littermates. Upon IRBP peptide stimulation, Tg-GKO lymphocytes did not produce IFN-γ, as expected, and instead produced high amounts of IL-17A. Most Tg-GKO mice developed spontaneous uveitis between 6 weeks and 4 months of age, whereas most IFN-γ-sufficient TCR Tg mice had detectable disease at 3 weeks and virtually all had uveitis by 2-3 months of age. In addition to delayed disease onset, Tg-GKO mice also showed decreased severity scores compared to their IFN-γ-sufficient IRBP TCR Tg counterparts.
Although IFN-γ appears to be dispensable for development of spontaneous EAU, delayed onset and reduced scores of disease in Tg-GKO mice point to a pathogenic role for this cytokine, that is not compensated for by increased levels of IL-17A.
This PDF is available to Subscribers Only