Ocular regulatory T cells distinguish monophasic from recurrent autoimmune uveitis

Three patterns of autoimmune (idiopathic) uveitis are seen in humans—monophasic, recurrent, and chronic. Chronic and recurrent uveitis are difficult to treat and they account for approximately 10% of legal blindness in the Western world.1 To understand the mechanisms that result in the natural resolution of monophasic uveitis and, thus, to identify optimal therapeutic strategies for recurrent or chronic uveitis, we previously generated experimental animal models of autoimmune uveitis with characteristics of the human disease.2–4 The major pathogenic events in experimental autoimmune uveitis (EAU) are initiated by the activation of T cells reactive with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP).5,6 Activated T cells have an increased ability to enter the target organ7 and to produce cytokines and chemokines to recruit other inflammatory cells that result in retinal tissue damage. Immunization with the immunodominant 1177–1191 peptide (R16) of IRBP results in monophasic disease in the Lewis rat; intraocular inflammation appears on day 8, lasts for 2 weeks, and spontaneously resolves. In contrast, the adoptive transfer of R16-specific T cells in Lewis rats results in recurrent disease that starts on day 4, with repeated recurrences for the next 2 to 3 months. These two models provide us with useful tools for studying the regulation of pathogenic effector T cells in vivo. A number of mechanisms are likely to contribute to recovery from autoimmune disease, including uveitis.8–10 Recent studies have demonstrated that among CD4 T cells, a subset expressing CD25 has strong suppressor activity.11,12 These naturally arising CD4+CD25+ regulatory T cells (Tregs) are powerful inhibitors of T-cell activation in vivo and in vitro, acting partially through IL-10 or transforming growth factor β (TGF-β)13,14; they also contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses. Their depletion or alteration of function leads to the development of autoimmune disease in otherwise healthy animals.15 The eye is the prototypic immunoprivileged organ. The ability of the ocular microenvironment, especially the aqueous humor (AqH),16 to suppress immune effector responses and inflammation is believed to be important to the existence of ocular immune privilege.16–18 Normal AqH displays many immunosuppressive and anti–inflammatory properties in vitro. With regard to adaptive immunity, AqH suppresses T-cell activation after ligation of the T-cell receptor (TCR) by antigen, inhibiting the proliferation of T-effector cells and the secretion of IFN-γ.17 It also alters the functional program of TCR ligand–activated, primed T cells, converting the cells to TGF-β–producing regulatory cells.19 Numerous immunomodulatory factors, such as TGF-β2,20,21 α-melanocyte–stimulating hormone,22 vasoactive intestinal peptide,23 calcitonin gene-related peptide,24 macrophage migration inhibitory factor,25 and IL-10,26 account for the immunosuppressive properties of AqH. This study provides evidence that Treg cells mediate spontaneous recovery from an active disease process in the target organ.