B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease.
B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease.
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B7H1/CD80 相互作用增强 PD-1 依赖性 T 细胞凋亡并改善移植物抗宿主病
DOI：
10.4049/jimmunol.1402157
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发表时间：
2015-01-15
期刊：
影响因子：
--
通讯作者：
Zeng D
中科院分区：
文献类型：
--
作者：
Deng R;Cassady K;Li X;Yao S;Zhang M;Racine J;Lin J;Chen L;Zeng D
B7H1(PD-L1)与其两个配体PD-1和CD80在T细胞上的相互作用在控制T细胞的激活、增殖、无能和凋亡中起着关键作用。然而，这两条途径之间的相互作用仍然未知。利用移植物抗宿主病的同种异体免疫应答模型，我们报道：1)比较野生型和PD-1CD4+常规T细胞在WT和B7H1−/−受体中的增殖和凋亡，发现B7H1/−/−相互作用本身促进T细胞的增殖，这种相互作用通过B7H1/PD-1相互作用介导T细胞的凋亡。这一观察结果在体外混合淋巴细胞反应试验中进行了总结。2)抗B7H1单抗特异性阻断B7H1/CD80轴，减少WT-异体反应性Tcon细胞增殖、IL-2产生、PD-1表达和细胞凋亡，导致GVHD加重。相反，特异性阻断B7H1/CD80相互作用可减少供者PD-1−/−TCON细胞的增殖，而不影响细胞凋亡，从而改善移植物抗宿主病。3)将B7H1融合到免疫球蛋白Fc结构域(B7H1-Ig)，在体内注射B7H1-Ig质粒，通过促进WT同种异体反应性Tcon细胞的增殖和凋亡来改善GVHD。相反，B7H1-Ig治疗对细胞凋亡无影响，但促进PD-1−/−T细胞增殖，加重移植物抗宿主病。这些结果表明，B7H1/CD80相互作用促进了Tcon细胞的增殖、IL-2的产生和PD-1的表达，从而导致B7H1/PD1通路介导的细胞凋亡增加。此外，通过结合PD-1和CD80，B7H1-Ig可以成为下调T细胞免疫反应的强大治疗剂。
Interactions of B7H1 (PD-L1) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report here that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1−/− CD4+ conventional T (Tcon) cells in WT and B7H1−/− recipients has revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction. This observation was recapitulated in an in vitro mixed lymphocyte reaction assay. 2) Specific blockade of the B7H1/CD80 axis by anti-B7H1 mAb reduces WT-alloreactive Tcon cell proliferation, IL-2 production, expression of PD-1, and apoptosis, resulting in worsening GVHD. In contrast, specific blockade of B7H1/CD80 interaction reduces donor PD-1−/− Tcon cell proliferation without impact on apoptosis, resulting in ameliorating GVHD. 3) B7H1 fused to an immunoglobulin Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1-Ig plasmid, ameliorates GVHD by augmenting proliferation and apoptosis of WT- alloreactive Tcon cells. Conversely, B7H1-Ig treatment has no impact on apoptosis but augments PD-1−/− T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 interaction augments Tcon cell proliferation, IL-2 production, and expression of PD-1, which leads to increased apoptosis mediated by the B7H1/PD1 pathway. Additionally, by engaging both PD-1 and CD80, B7H1-Ig can be a powerful therapeutic reagent for down-regulating the T cell immune response.
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影响因子：
32.4
作者：
Dong, HD;Zhu, GF;Chen, LP
通讯作者：
Chen, LP
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
17.1
作者：
Amarnath S;Mangus CW;Wang JC;Wei F;He A;Kapoor V;Foley JE;Massey PR;Felizardo TC;Riley JL;Levine BL;June CH;Medin JA;Fowler DH
通讯作者：
Fowler DH
影响因子：
56.9
作者：
SMITH, KA
通讯作者：
SMITH, KA