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Kevin M. Brown, Elizabeth Charles, Sunil Joshi, David M. Sherry, Muayyad R. Al-Ubaidi, Mark Lang, Ira Blader; Retinal Neurons Express MHC Class II and PD-L1 to Suppress Activated T cells in Toxoplasma gondii-Infected Eyes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3390.
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The retina is an immune-privileged tissue that suppresses immune surveillance and activation. Upon infection by pathogens, the immune-privileged state of the retina must be suppressed or overcome to control the infection. Our lab has used infections with the retinal parasite Toxoplasma gondii as a model for immune privilege regulation. Because retinal damage in Toxoplasma-infected eyes is due to dysregulated CD4+ T cells, the goal of this study was to determine how intraretinal CD4+ T cells are regulated.
To study acute infection, mice were intravitreally-injected with Toxoplasma parasites or vehicle alone. Eyes were enucleated 6 days post-injection and subjected to flow cytometric, immunohistochemical, and functional analyses. To study chronic infections, WT or PD-L1-/- mice were infected intraperitoneally with Toxoplasma parasites. Eyes were enucleated 30 days post-infection and analyzed by flow cytometry and histochemistry. Neuroretinal immunoregulatory function was assessed in vitro using the murine cone photoreceptor cell line 661W.
Acute Toxoplasma infection leads to MHC class II expression on infiltrating leukocytes as well as most types of retinal neurons. Nearly all MHC class II+ cells expressed the co-inhibitory molecule programmed death-ligand 1 (PD-L1), but not positively acting co-stimulatory molecules CD80, CD86, or ICOS-L. Total retinal cells from Toxoplasma-infected mouse eyes were able to suppress T cell activation in a PD-L1-dependent manner. Functionally, loss of PD-L1 resulted in increased retinal pathology and T cell infiltration compared to WT control mice. IFNγ was critical for the induction of both MHC class II and PD-L1. Finally, IFNγ-primed 661W photoreceptors expressed MCH class II and PD-L1 and were able to robustly inhibit CD4+ T cell activation.
The upregulation of MHC class II and PD-L1 in Toxoplasma-infected retinas appears be to be an important mechanism regulating CD4+ T cell infiltrates. Based on these data, we propose a novel function for retinal neurons - inducible regulators of retinal immune privilege.
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