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D. J. Lee, A. W. Taylor; The Natural Emergence of Regulatory Immunity During EAU Involves a MC5r Dependent Change in the APC. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5164.
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Previously, we have reported that the spleens of post-EAU (experimental autoimmune uveitis) mice have ocular autoantigen specific regulatory T cells (Treg cells). This regulatory activity can be transferred only when the Treg cells are restimulated with spleen post-EAU antigen presenting cell (APC). In addition, the induction of this post-EAU regulatory activity is dependent on expression of the Melanocortin 5 Receptor (MC5r). Therefore, we assayed for the possibility that the requirement for MC5r in the induction of the post-EAU regulatory immunity is to generate the emergence of an APC that promote Treg cell activation.
C57BL/6 and MC5r knockout (MC5r(-/-)) mice were immunized to induce EAU with IRBP peptide 1-20 in CFA. A fundus exam was done every 3-4 days until resolution. Post-EAU spleen wild-type (WT) T cells were activated with post-EAU spleen MC5r(-/-) APC, and the reciprocal activation scheme was performed. The activated T cells and post-EAU APC were adoptively transferred into naive recipient mice, immunized for EAU, and the course of disease was followed. To assay the functionality of the APC during the course of EAU, on days 24, 41, 54, and 80 after immunization for EAU APCs were isolated from the spleens of WT EAU mice, and were assayed for their ability to stimulate IFN-γ and TGF-β production by IRBP-specific effector T cells with intracellular staining flow cytometry.
Transfer of post-EAU MC5r(-/-) T cells and post-EAU WT APC suppressed disease in the recipient mice. Whereas, post-EAU wild-type T cells and post-EAU MC5r(-/-) APC only delayed the onset of EAU. IFN-γ expression showed a decrease when T cells were incubated with APC from day 54 and 80 of EAU compared to IFN-γ expression in T cells incubated with APC from day 24 and 41 of EAU. TGF-β expression in T cells remained unchanged when incubated with APC from different times during EAU.
Our results show a role in the expression of MC5r in the emergence of post-EAU regulatory APC. Furthermore, throughout the course of EAU there is a sequential change in the type of T cell stimulated by the spleen APC. These results suggest the melanocortin pathway is involved in the emergence of regulatory immunity during EAU associated with a change in APC stimulation of ocular autoantigen reactive T cells.
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