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D. S. Gregerson, N. D. Heuss, U. Lehmann, S. W. McPherson; Dissociation of Treg Activity for Effector Functions in Mice With and Without Retinal Beta-Galactosidase Expression. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5919.
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© ARVO (1962-2015); The Authors (2016-present)
We previously showed that regulatory T cells (Tregs) developed in mice based on the retinal expression of beta-galactosidase (Bgal) in retinal photoreceptor cells. The activity of these Tregs was compared to that of Tregs isolated from wild-type mice, or from T cell receptor transgenic (Tg) mice specific for Bgal (BgalTCR mice).
Tg expression of Bgal controlled by the retinal photoreceptor cell arrestin promoter (arrBgal mice) was used as the source of retinal antigen (Ag), and as a source of both Bgal- and retinal Ag-specific Tregs. BgalTCR mice were used as a source of naive or Ag-experienced CD4 T cells, and Bgal-specific Tregs. Tregs were also isolated from normal, non-Tg mice. Isolation of Tregs was based on CD25 expression. The activities of the Tregs were tested by assaying for their effects on EAU induction, DTH, lymphopenia induced proliferation (LIP), and Ag-stimulated cytokine production.
CD25+ Tregs from wild-type or BgalTCR mice were both capable of inhibiting EAU, consistent with the presence of retinal Ag-specific Tregs, as well as Bgal-specific Tregs, acting locally to limit pathogenesis of EAU. Since several retinal Ags, including IRBP co-localize with the Bgal target of the effector T cells, bystander mechanisms appear to contribute to the inhibition of disease. LIP of BgalTCR T cells was also inhibited by retinal Ag-specific Tregs. Conversely, Bgal-specific Tregs were required to inhibit the ear swelling assay for DTH. Since the ear swelling assay is done by injection of purified Bgal Ag the results indicate that Ag-specific, but not bystander mechanisms were needed to limit DTH. Bgal-specific Tregs were required to inhibit the cytokine production of BgalTCR T cells stimulated in vitro, and support the need for Ag specificity if other specificities are not present.
These results are consistent with the hypothesis that the contributions of Tregs with multiple Ag specificities provide protection for the retina from inflammation due to autoimmunity to a single retinal self-Ag. This strategy would promote protection for a vital tissue.
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