Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
复制标题
DOI：
10.1182/blood-2007-12-127449
复制
发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Sykes, Megan
中科院分区：
文献类型：
--
作者：
Haspot, Fabienne;Fehr, Thomas;Sykes, Megan
尽管程序性死亡 1 (PID-11) 和配体 PD-L1 之间的相互作用已被证明在慢性感染或缺乏 CD4 帮助的情况下介导 CD8 细胞耗竭，但该途径在减弱早期同种异体 CD8 细胞反应中的作用尚未确定。我们证明，在需要 Cl 细胞并最终导致 CD8 细胞缺失的模型中，需要 PD-1/PD-L1 途径来快速耐受同种异体反应性 CD8 细胞。该方案涉及在低剂量全身照射和抗 CD154 抗体调理后进行同种异体骨髓移植 (BMT)。耐受的供体反应性 T 细胞受体转基因 CD8 细胞在删除之前处于流产激活状态，显示出激活标记的早期和延长表达（与排斥性 CD8 细胞相比），同时在移植后第 4 天功能性沉默。尽管耐受和排斥同种异体反应性 Cl 细胞均上调 PD-1，但 CD8 细胞耐受性依赖于 PD-1/PD-L1 通路。相比之下，在使用抗 CD154 进行 BMT 后，CD4 细胞的耐受性独立于该途径。这些研究证明了 CD4 和 CD8 耐受性要求之间的二分法，并确定了 PD-1 通过删除机制在同种异体反应性 T 细胞群快速耐受中的作用。
Although interaction between programmed death-1 (PID-11) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires Cl cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T-cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive Cl cells up-regulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism.