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D. S. Gregerson, N. D. Heuss, U. Lehmann, S. W. McPherson; Evidence for Recognition of a Retinal Antigen by Naive CD4 T Cells Leading to Immunoregulation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2509.
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Thymic expression of self-Ags is known to generate regulatory T cells (Tregs) that prevent spontaneous autoimmune disease. However, the contribution of endogenous, tissue-specific Ags expressed in the periphery to the generation of Tregs or anergic T cells is uncertain.
Transgenic expression of beta-galactosidase (Bgal) on a retinal photoreceptor cell promoter was used as the source of retinal antigen. TCR transgenic mice producing CD4 T cells specific for Bgal (TCRBgal) were used as a source of naive or antigen-experienced CD4 T cells. The role of retina as the source of Ag was examined by three strategies. First, enucleation followed by lympho-ablation; second, CD11c+ cells were recruited to the retina by an optic nerve crush; and third, phenotypic and functional analysis of purified CD25+ and CD25- TCRBgal T cells recovered from Rag(-/-) versus Rag(-/-) x retinal Bgal double Tg recipients of CD25- donor TCRBgal T cells.
Transgenic expression of Bgal on a retinal photoreceptor cell promoter generated a spontaneous immunoregulatory response that depressed development of immune responses to Bgal following systemic immunization with Bgal. The regulation was transferred by CD3+4+25+ Tregs. Analysis of the enucleated retinal Bgal mice by an ear swelling assay for DTH showed that they failed to regenerate Tregs. Recruitment of DCs to the retina following the optic nerve crush abrogated the regulatory response. Finally, anergic T cells and Tregs were found to develop in mature, peripheral CD4+25- T cells after transfer to Rag-deficient mice with retinal Bgal expression.
These results are the first to show that retinal expression of very small amounts of a tissue-specific Ag can alter mature T cell responsiveness to that Ag outside of the thymus. Although phenotypic changes measurable by flow cytometry were not found, functional assays revealed the generation of T cells with altered function in the periphery. This property distinguishes them from regulatory cells generated in the thymus.
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