Author(s): Hori J, Taniguchi H, Wang M, Oshima M, Azuma M
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Abstract PURPOSE: The pathway between the glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and GITR ligand (GITRL) has been shown to control the function of regulatory T cells (Treg). The present study was conducted to investigate the role of this pathway and Treg in establishing immune privilege status for corneal allografts. METHODS: Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c mice, and graft survival was assessed. A separate set of BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allo-specific anterior chamber-associated immune deviation was assessed. Recipients were intraperitoneally administrated anti-GITRL, anti-CD25 monoclonal antibodies (mAb), or control immunoglobulin (IgG). Expressions of GITRL, GITR, and Foxp3 in the allografts were assessed. In vitro, cornea pretreated with anti-GITRL mAb or control IgG was incubated with T cells, and destruction of corneal endothelial cells and the population of Foxp3(+)CD25(+)CD4(+) T cells were assessed. RESULTS: GITRL was expressed constitutively in the cornea and iris-ciliary body. GITRL-expressing allografts were infiltrated with Foxp3+GITR+CD25+CD4(+) T cells. Blockade of GITRL did not affect allo-specific ACAID but led to infiltration of Foxp3(-)CD4(+) T cells and allograft rejection. Depletion of CD25+CD4(+) Treg also accelerated allograft rejection. Destruction of corneal endothelial cells by T cells was significantly enhanced in GITRL-blocked cornea compared with control cornea. Foxp3+CD25+CD4(+) T cells were increased after incubation with GITRL-expressing cornea, but not with GITRL-blocked cornea. CONCLUSIONS: Presence of Foxp3+CD25+CD4(+) Treg in the allograft is necessary for allograft survival. GITRL-dependent expansion of Treg within the cornea is one mechanism underlying immune privilege in corneal allografts.
This article was published in Invest Ophthalmol Vis Sci
and referenced in Journal of Clinical & Experimental Ophthalmology