Characterization of IL-17+ interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis.

Experimental autoimmune uveitis (EAU) is a T cell-mediated autoimmune disease that serves as a model for several posterior uveitides, such as Behcet disease, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroidopathy, and sympathetic ophthalmia.1,2 The histopathology of EAU is characterized by posterior retinal and choroidal inflammation, granuloma formation, vasculitis, photoreceptor damage, vitreitis, and varying degrees of anterior uveitis.2 EAU is induced in animals by immunization with retinal antigens or by the adoptive transfer of retinal antigen-specific T lymphocytes.3,4 Among the ocular antigens known to induce EAU in rodent models are interphotoreceptor retinoid-binding protein (IRBP)5 and the soluble retinal antigen (S-antigen).6,7 Thus far, it is thought that the major subsets of pathogenic autoreactive T cells produce proinflammatory cytokines, including IFN-γ and IL-2, and belong to the Th1-type of CD4 T cells.8 Recent studies have shown that a specific autoreactive T-cell subset that produces IL-17, but not IFN-γ or IL-4, is crucially involved in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, experimental autoimmune encephalomyelitis (EAE),9–11 and other allergic diseases,12–14 especially during the chronic phase. IL-17–deficient mice are resistant to an arthritislike disease15,16 and have impaired host defense against microbial infection and an increased incidence of acquired delayed-type hypersensitivity.15 In addition, autoimmune-prone mice become disease resistant after they are treated with an IL-17R antagonist.17 To determine the role of IL-17+ T cells in the pathogenesis of EAU and the interrelationship between previously characterized uveitogenic T-cell subsets and IL-17+ T cells, we studied the induction and pathologic function of IL-17+ T cells. We were particularly interested in determining whether IL-17 was expressed only by CD4 autoreactive T cells or also by CD8 autoreactive T cells and in comparing the pathogenic effect of IL-17+ T cells specific for the uveitogenic antigen with that of nonspecific IL-17+ T cells. We showed that CD4 and CD8 autoreactive T cells in EAU were equally capable of expressing IL-17 and that IRBP-specific T cells preferentially expressed IL-17 when they were expanded by IL-23, whereas IFN-γ– expressing cells were dominant when the T cells were cultured with IL-2. We also showed that both sets of expanded T cells were uveitogenic. Comparison of IL-17+ T cells elicited by antigen-specific stimulation in vitro with those elicited by antigen-nonspecific activation (anti-CD3 antibody) demonstrated that only antigen-specific IL-17+ T cells were uveitogenic. Finally, we showed that the ligation of Toll-like receptor (TLR) greatly enhanced the activation of IL-17–producing T cells in vivo and in vitro. Our results provide direct evidence that IL-17+ autoreactive T cells elicited by uveitogenic antigen are pathogenic, that the number and activation of these T cells is regulated by available cytokines, that the activation of such T-cell subsets is regulated by factors other than autoantigen, such as mycobacterial components in complete Freund adjuvant (CFA), and that pertussis toxin (PTX), which is essential for the induction of EAU in animal models, promotes the activation of IL-17+ autoreactive T cells.