Spontaneous Uveitis in IRBP T Cell Receptor Transgenic Mice

Abstract

Purpose: : To study effector and regulatory T cells involved in uveitis, we generated transgenic (Tg) mice on the EAU-susceptible B10.RIII background that express a T cell receptor (TCR) specific to the uveitogenic retinal protein IRBP.

Methods: : IRBP161-180-specific TCR cDNAs were cloned from a uveitogenic T cell line. Transgenic constructs incorporating the TCR alpha and beta chains under CD2 or MHC class I promoters, respectively, were microinjected together into B10.RIII embryos. Leukocyte profiles in lymphoid tissues and eyes were examined by flow cytometry. The IRBP-specific T cells were detected with 161-180/IA^r/Ig dimers. Ocular pathology was evaluated by fundoscopy and histology.

Results: : The peripheral T cell repertoire of IRBP TCR Tg mice contained 15-30% IRBP-specific CD4⁺ T cells, as judged by binding of the Ag-specific dimers. These cells proliferated to IRBP161-180 and upon activation transferred EAU to naïve wild type recipients. Importantly, IRBP TCR Tg mice rapidly developed spontaneous uveitis, starting around 5 weeks of age and reaching 80% incidence by 8 weeks. Nevertheless, the proportion of memory CD4⁺ T cells in the IRBP-specific population was substantially lower than in the polyclonal population, suggesting differences in availability of the respective priming antigens. In contrast, most of the eye-infiltrating CD4⁺ T cells had a memory phenotype. The ocular inflammatory infiltrate was composed of monocytes, granulocytes and lymphocytes, including Th1, Th17 and T regulatory cells, as detected by intracellular staining for IFN-gamma, IL-17 and Foxp3, respectively. IRBP-specific T regulatory cells were enriched in the eye compared to the periphery, suggesting their retention or conversion locally in the eye.

Conclusions: : The IRBP TCR Tg mice provide a new model of spontaneous uveitis with early onset that circumvents the limitations of active immunization and the use of adjuvants. These mice are not only a useful tool to examine IRBP-specific T cell responses but also will serve as a valuable animal model to further understand the mechanisms involved in uveitis.

Keywords: uveitis-clinical/animal model • autoimmune disease • inflammation