Molecular mechanisms of immune privilege of corneal transplantation

程序性死亡-1(PD-1)共刺激通路在免疫反应和外周耐受调节中发挥作用。我们研究了这一途径在建立小鼠角膜移植免疫豁免状态中的作用。B7-H1在眼部，即角膜、虹膜睫状体和视网膜中有结构性表达，但不表达B7-DC或PD-1。同种异体角膜移植后，PD-1~+CD_4~+T细胞与B7-H_1~+角膜内皮细胞黏附。阻断PD-1或B7-H1，但不阻断B7-DC，导致同种异体角膜移植加速排斥反应。在表达B7-H1的同种异体角膜移植物中，可观察到浸润性的PD-1^+CD4^+或CD8^+T细胞的凋亡，之后才有同种异体移植的接受。相反，B7-H1阻断抑制了浸润性PD-1^+T细胞的凋亡，从而导致同种异体移植排斥反应。在体外，抗B7-H1抗体可增强同种异体反应性T细胞对角膜内皮细胞的破坏作用。这是首次证明B7-H1的结构性表达在同种异体角膜移植物存活中起关键作用。表达于角膜内皮细胞上的B7-H1通过诱导角膜内效应性T细胞的凋亡来维持角膜移植物的长期接受性。

The programmed death-1 (PD-1) costimulatory pathway has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in establishing an immune privilege status of corneal allografts in mice. B7-H1, but not B7-DC or PD-1, was expressed constitutively in the eye, i.e., cornea, iris-ciliary body and retina. After corneal allografting, PD-1^+ CD4^+ T cells infiltrated and adhered with B7-H1^+ corneal endothelium. Blockade of PD-1 or B7-H1, but not B7-DC, led to accelerated corneal allograft rejection. In B7-H1-expressing corneal allografts, apoptosis of the infiltrating PD-1^+ CD4^+ or CD8^+ T cells was observed, after which there was allograft acceptance. In contrast, B7-H1 blockade suppressed apoptosis of infiltrating PD-1^+T cells, which led to allograft rejection. In vitro, destruction of corneal endothelial cells by alloreactive T cells was enhanced when the cornea was pre-treated with anti-B7-H1 antibody. This is the first demonstration that the constitutive expression of B7-H1 plays a critical role in corneal allograft survival. B7-H1 expressed on corneal endothelial cells maintains long-term acceptance of the corneal allografts by inducing apoptosis of effector T cells within the cornea.