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Sung-Hye Kim, Chengrong Yu, Bernadette Marrero, Charles E. Egwuagu; IRF-8 Antagonizes Th17 and Tc17 Expansion and Restrains Th17 Inflammatory Responses During Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2535.
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© ARVO (1962-2015); The Authors (2016-present)
Interferon Regulatory Factor (IRF) factors play important roles in host immunity. Currently, there are nine known IRFs. They are expressed ubiquitously, except IRF-8 whose expression is restricted to myeloid and B cells. However, when naïve T cells are stimulated with Ag, IRF-8 is copiously induced. Nonetheless, the significance of IRF-8 expression in activated T cells is unknown. In this study, we have investigated the function of IRF-8 in activated T cells of mutant mice withtargeted deletion of IRF-8 in CD4 and CD8 T cells (CD4/CD8KO).
We generated the CD4/CD8 KO mouse strain by breeding IRF-8 floxed mice (IRF-8fl/fl) mice (kind gift from Herbert Morse, NIH) with CD4/Cre mice. Deletion of IRF-8 was confirmed by western blot analysis of TCR-activated CD4+and CD8+ T cells from the CD4/CD8KO mice. Homozygous CD4/CD8 IRF-8KO mouse strain was established by several cycles of brother-sister mating. Effector functions ofCD4/CD8KO T cells were characterized by Thymidine-incorporation assay, CFSE labeling, RT-PCR, western blot analysis, intracellular cytokine staining assays. In vivo functions of IRF-8 were investigated by active immunization of WT or CD4/CD8KO mice with IRBP/CFA and we examined whether IRF-8 in T cells can influence the development or susceptibility to experimental autoimmune uveitis (EAU). We monitored the progression and severity of EAU by fundoscopy and histology.
Compared to WT, CD4/CD8KO mice developed a more severe EAU, which is characterized by massive infiltration of cells into the retina, papilledema, focal retinitis, retinal vasculitis and multifocal-choroiditis. Compared to WT, CD4/CD8KO T cells produced three-folds and four-folds higher levels of IL-17-expressing Th17 and Tc17 cells, respectively, which may have contributed to the severe ocular pathology. CD4+ and CD8+ T cells from CD4/CD8KO exhibited higher proliferative capacity and were more susceptible to apoptosis.
Our data suggest that IRF-8 expression in activated T cells antagonizes Th17 and Tc17 expansion and restrains excessive Th17 inflammatory responses that occur during autoimmune disease. On the other hand, enhanced apoptosis manifested by CD4/CD8KO T cells suggests that IRF-8 may enhance productive immune responses against pathogens (e.g. S.aureus, S. Pneumoniae, Candida albicans and other fungi) by conferring stability to the Th17 and Tc17 T cell subsets.
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