Blockade of PD-1/PD-L1 increases effector T cells and aggravates murine chronic graft-versus-host disease
Blockade of PD-1/PD-L1 increases effector T cells and aggravates murine chronic graft-versus-host disease
复制标题
阻断 PD-1/PD-L1 会增加效应 T 细胞并加重小鼠慢性移植物抗宿主病
DOI：
10.1016/j.intimp.2022.109051
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发表时间：
2022-07-16
影响因子：
5.6
通讯作者：
Pan, Bin
中科院分区：
文献类型：
--
作者：
Liang, Yiwen;Shen, Jingyi;Pan, Bin
T细胞介导的免疫病理学对于慢性移植物抗宿主病（cGVHD）的发病机制至关重要，慢性移植物抗宿主病是异基因造血细胞移植后的常见并发症。程序性死亡-1（PD-1）调节T细胞的长期存活和功能衰竭，可能在调节cGVHD中发挥作用。我们检查了cGVHD小鼠T细胞上的PD-1表达，并测试了PD-1抗体对小鼠同种异体移植模型中cGVHD严重程度的影响。我们还使用小鼠移植物抗肿瘤（GVT）模型来探索肿瘤细胞来源的PD-L1如何影响GVT效应和cGVHD的发生。在发生cGVHD的小鼠中，CD 4（+）T -细胞上的PD-1荧光强度增加。与PD-1（低）T细胞相比，PD-1（高）T细胞表达更高水平的IFN γ和IL-17。给予PD-1抗体增加了Th 1，Th 17和Tc 1细胞的比例，但降低了同种异体移植小鼠中Treg细胞的比例。PD-1抗体降低了受体的存活率并诱导了严重的肺cGVHD。在GVT模型中，A20肿瘤细胞中PD-L1的敲低增强了GVT效应，但增加了cGVHD。体外研究表明，肿瘤细胞中PD-L1的敲低增加了T细胞的细胞毒性，减少了T细胞的凋亡。肿瘤细胞中PD-L1的敲低增加了磷酸化AKT、Bcl-2和Mcl-1的蛋白水平，但降低了共培养的同种异体T细胞中巴克和Bax的蛋白水平。总之，在经历cGVHD的小鼠中，T细胞上PD-1的表达增加。PD-1/PD-L1通路的干预对cGVHD和GVT效应的发生有显著影响。
T-cells mediated immunopathology is crucial for pathogenesis of chronic graft-versus-host disease (cGVHD), a common complication following allogeneic hematopoietic cell transplantation. Programmed death-1 (PD-1) regulates long-term survival and functional exhaustion of T-cell which might play a role in regulating cGVHD. We examined PD-1 expression on T cells of cGVHD mice and tested the impact of a PD-1 antibody on severity of cGVHD in murine allotransplant models. We also used a murine graft-versus-tumor (GVT) model to explore how tumor cell-derived PD-L1 affect the GVT effect and occurrence of cGVHD. PD-1 fluorescence intensity on CD4(+) T -cells increased in mice developing cGVHD. PD-1(High) T cells expressed higher levels of IFN gamma and IL-17, comparing with PD-1(Low )T cells. Giving the PD-1 antibody increased proportions of Th1, Th17 and Tc1 cells, but decreased proportion of Treg cells in allotransplant mice. The PD-1 antibody decreased survival of recipients and induced severe lung cGVHD. In the GVT model, knockdown of PD-L1 in A20 tumor cells enhanced GVT effect but increased cGVHD. In vitro study showed knockdown of PD-L1 in tumor cells increased cytotoxicity of T cells and reduced apoptosis of T cells. Knockdown of PD-L1 in tumor cells increased protein levels of phosphorylated AKT, Bcl-2 and Mcl-1, but decreased protein levels of Bak and Bax in co-cultured allogeneic T cells. In conclusion, expression of PD-1 on T cells increased in mice undergoing cGVHD. Intervention of the PD-1/PD-L1 pathway showed a significant impact on occurrence of cGVHD and GVT effect.