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Reiko Horai, Phyllis B Silver, Jun Chen, Carlos Zárate-Bladés, Wai Po Chong, Ru Zhou, Yingyos Jittayasothorn, Sonia Nguyen, Chi-Chao Chan, Rachel R Caspi; Spontaneous ocular autoimmunity in mice expressing a transgenic T cell receptor specific for a retinal autoantigen. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2499.
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© ARVO (1962-2015); The Authors (2016-present)
The EAU model, induced by immunization of mice with the retinal protein IRBP or its peptides, has been very useful to study basic mechanisms of ocular inflammation. However, it is inadequate for some types of studies, due to the need for active immunization in the context of strong bacterial adjuvants. To understand the pathogenesis of uveitis under more physiological settings, we generated transgenic mice that express a retina-specific T cell receptor (TCR).
Transgenic constructs incorporating the IRBP161-180-specific TCR α and β chains under CD2 or MHC class I promoters, respectively, were co-injected into embryos of EAU-susceptible B10.RIII mice. IRBP-specific T cells were detected with an Ag-MHC class II-Ig dimer. Ocular pathology was evaluated by fundoscopy and histology.
Three lines of IRBP TCR Tg mice (R161H, M, L) were established that express different levels of the transgenic TCR and show different proportions of IRBP-specific CD4+ T cells in their peripheral repertoire. Importantly, two of the lines, R161H and R161M, rapidly developed spontaneous uveitis, reaching 100% incidence by 2 and 3 months of age, respectively, whereas the third line, R161L, appeared “poised” and only developed appreciable disease upon immune perturbation by microbial stimuli. Susceptibility roughly paralleled expression of the transgenic TCR. Peripheral IRBP-specific CD4+ T cells displayed a naïve phenotype, whereas T cells infiltrating uveitic eyes mostly showed an effector/memory phenotype, and included Th1, Th17 as well as T regulatory (Treg) cells. Retina-specific Treg cells appeared to have been peripherally converted rather than thymically derived. T cells from R161 mice responded to IRBP and transferred uveitis to naïve recipients, providing a source of retina-specific T cells for a variety of basic studies. Examples that will be presented include the role of commensal microbiota in uveitogenic T cell priming, as well as effector cytokines and regulatory mechanisms in uveitis.
R161 lines of transgenic mice provide a new and valuable model of spontaneous autoimmune uveitis that allows to study natural triggers and basic mechanisms involved in breakdown of immune homeostasis in the eye. This model may also be useful for the development of therapeutic strategies for uveitis.
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