Chen Luqiu, Hussien Yassir, Hwang Kwang Woo, Wang Ying, Zhou Ping, Alegre Maria-Luisa
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Transpl Int. 2008 Jan;21(1):21-9. doi: 10.1111/j.1432-2277.2007.00536.x.
Program death-1 (PD-1), an inhibitory receptor upregulated on T cells upon TCR stimulation, has been shown to attenuate a number of immune responses in vivo, including acute allograft rejection. We tested whether constitutive expression of PD-1 would further inhibit allograft rejection. To this end, we generated transgenic mice expressing T-cell-restricted PD-1 under the control of the Lck proximal promoter and CD2 locus control. PD-1 transgenic (PD-1-Tg) mice did not develop gross abnormalities of thymic development and displayed normal numbers of thymocyte subsets and peripheral T cells. In vitro, PD-1-Tg T cells had reduced proliferative and cytokine secretion capacity upon TCR stimulation and cross-linking of PD-1 resulted in diminished phosphorylation of protein kinase C-theta and Akt, as well as increased activation of the phosphate and tensin homolog. However, only T-cell responses to minor but not major mismatches were reduced in vitro. Similarly, PD-1-Tg mice exhibited prolonged survival of cardiac allografts only in mice transplanted with heart allografts expressing multiple minor mismatches and treated with suboptimal doses of cyclosporine A. We conclude that genetic engineering of T cells to express PD-1 constitutively has only a mild impact on allograft survival.
程序性死亡蛋白 1（PD - 1）是一种在TCR刺激后在T细胞上上调的抑制性受体，已证明其可在体内减弱多种免疫反应，包括急性同种异体移植排斥反应。我们测试了PD - 1的组成性表达是否会进一步抑制同种异体移植排斥反应。为此，我们构建了在Lck近端启动子和CD2基因座控制下表达T细胞限制性PD - 1的转基因小鼠。PD - 1转基因（PD - 1 - Tg）小鼠没有出现胸腺发育的明显异常，胸腺细胞亚群和外周T细胞数量正常。在体外，PD - 1 - Tg T细胞在TCR刺激后增殖和细胞因子分泌能力降低，PD - 1的交联导致蛋白激酶C - θ和Akt的磷酸化减少，以及磷酸酶和张力蛋白同源物的激活增加。然而，体外只有T细胞对次要而非主要错配的反应降低。同样，PD - 1 - Tg小鼠仅在移植了表达多个次要错配的心脏同种异体移植物并用次优剂量环孢素A治疗的小鼠中表现出心脏同种异体移植物的存活时间延长。我们得出结论，对T细胞进行基因工程改造使其组成性表达PD - 1对同种异体移植物存活的影响较小。
