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Peripheral Induction of Tolerance by Retinal Antigen Expression¹

Department of Ophthalmology, University of Minnesota, Minneapolis, MN 55455

The contribution of peripheral expression of tissue-specific CNS Ags to the generation of tolerance is uncertain. To study this question, we examined mice transgenic (Tg) for expression of β-galactosidase (βgal) on the retinal photoreceptor cell arrestin promoter, in conjunction with TCR Tg mice producing CD4⁺ T cells specific for βgal (βgalTCR). Several strategies were used to test the hypothesis that βgal expressed in the retina supported thymus-independent tolerance and regulatory T cell development. Retinal expression generated an immunoregulatory response that depressed development of immune responses to βgal following systemic immunization with βgal. This regulation was transferable to naive mice by CD3⁺4⁺25⁺ T cells from naive retinal βgal⁺ donors. Experiments that removed the βgal⁺ retina by enucleation showed that subsequent development of a regulatory response was lost. Adoptive transfer of CD25^– βgalTCR T cells into retinal βgal Tg mice on the Rag^–/– background led to regulatory activity that limited lymphopenia-induced proliferation of βgalTCR T cells in mice with retinal expression of βgal and inhibited the ear-swelling assay for delayed type hypersensitivity. These results show that retinal expression of very small amounts of a tissue-specific Ag can generate tolerance that includes regulatory T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 EY011542dsg, R01 EY016376dsg, and T32 EY007133ul, Research to Prevent Blindness, Inc., and the Minnesota Lions and Lionesses Clubs.

² Address correspondence and reprint requests to Dr. Dale S. Gregerson, Department of Ophthalmology, University of Minnesota, 2001 6th Street Southeast, Minneapolis, MN 55455-3007. E-mail address: grege001{at}umn.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; EAU, experimental autoimmune uveoretinitis; DC, dendritic cell; DTH, delayed-type hypersensitivity; SPL, splenocyte; βgal, β-galactosidase; VSC 56, recombinant vaccinia virus expressing βgal; TSA, tissue-specific self-Ag; ONC, optic nerve crush; GFAP, glial fibrillary acidic protein; Tg, transgenic; IRBP, interphotoreceptor retinoid binding protein; LIP, lymphopenia-induced proliferation.