Abstract
Purpose: :
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).
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: immunomodulation/immunoregulation • autoimmune disease • immune tolerance/privilege