Iris Pigment Epithelium Suppresses T Cell Activation Through a Cell Contact-Dependent Mechanism that Uses B7.2 and CTLA-4

Abstract

Abstract: : Purpose: Ocular pigment epithelia (PE) play important, but poorly understood, roles in conferring immune privilege on the eye and in suppressing intraocular inflammation. Unlike cultured pigment epithelium from ciliary body and retina, iris PE suppresses T cell activation in vitro exclusively by a cell contact-dependent mechanism. The goal of this study is to identify the cell surface molecules responsible for suppression. Methods: PE cells were cultured separately from freshly explanted iris (IPE), ciliary body (CBPE), and retina (RPE) removed from wild type and B7.1, and B7.1/B7.2 KO mice. Tissue sections and cultured cells were examined by flow cytometry or immunohistochemistry and by RT-PCR for expression of B7.1 and B7.2. The cultured cells were assayed for capacity to suppress anti-CD3-driven activation (proliferation, IFNg secretion) of T cells from normal, CD28 KO, and CTLA-4 KO mice in the presence of reagents that interrupt co-stimulation via CD28 and CTLA-4. T cells exposed to PE cells were evaluated for their capacity to suppress activation of by stander T cells in secondary cultures. Results: All three PE cell types expressed B7.1, but only IPE expressed B7.2. All three PE cell types suppressed activation of T cells from normal and CD28 KO donors, but not CTLA-4 KO donors. Anti-B7.2 antibodies, as well as CTLA-Ig relieved suppression of T cell activation by IPE, but not by CBPE or RPE. IPE from B7.1/B7.2 KO mice suppressed T cell activation less efficiently than wild type or B7.1 KO IPE donors. IPE cells converted normal, but not CTLA-4 KO, T cells into regulators that suppress bystander T cell activation. Conclusions: Unlike cultured CBPE and RPE, IPE constitutively express B7.2 and suppress T cell activation via binding to CTLA-4. Since T cells exposed to B7.2 expressing IPE acquired regulatory function, ocular immune privilege arises in part because IPE provide T cells with signal 2 in a context that deviates them away from effector function into cells capable of regulatory other T cells.

Keywords: immune tolerance/privilege • iris • cell-cell communication