Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function.
Specific and high-affinity binding of tetramerized PD-L1 extracellular domain to PD-1-expressing cells: possible application to enhance T cell function.
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DOI：
10.1093/intimm/dxm059
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发表时间：
2007-07
影响因子：
4.4
通讯作者：
S. Terawaki;Yoshimasa Tanaka;T. Nagakura;Tamon Hayashi;Shiro Shibayama;Kaori Muroi;Taku Okazaki;B. Mikami;D. Garboczi;T. Honjo;N. Minato
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文献类型：
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作者：
S. Terawaki;Yoshimasa Tanaka;T. Nagakura;Tamon Hayashi;Shiro Shibayama;Kaori Muroi;Taku Okazaki;B. Mikami;D. Garboczi;T. Honjo;N. Minato
负性共刺激受体，程序性细胞死亡1（PD-1），在活化的T细胞上被诱导，并在与其配体PD-L1和PD-L2接合时传递抑制信号，这些配体在各种体细胞和某些癌症上表达。越来越多的证据表明，干扰PD-1-PD-L1相互作用可能导致癌症和慢性病毒感染中缺陷T细胞功能的恢复。在此，我们建立了生产大量小鼠PD-1（mPD-1）和PD-L1的复性重组胞外结构域蛋白的方法。虽然单体mPD-1和小鼠PD-L1（mPD-L1）仅与表达其对应蛋白的细胞发生少量相互作用，但它们的四聚化显著增强了亲和力，mPD-L1四聚体的K（d）比相应单体的K（d）低近100倍。mPD-L1四聚体的亲和力甚至高于高亲和力抗PD-1 mAb，并且其有效地抑制mPD-L1/Fc嵌合蛋白与mPD-1（+）细胞的结合。在功能上，mPD-L1四聚体在体外显著增强T细胞对特定靶细胞的增殖反应以及细胞毒活性。结果表明，寡聚PD-L1胞外结构域可能提供一种潜在的手段来恢复人类癌症和病毒感染中的T细胞功能。
The negative co-stimulatory receptor, programmed cell death 1 (PD-1), is induced on activated T cells and delivers inhibitory signals upon engagement with its ligands PD-L1 and PD-L2, which are expressed on various somatic cells and certain cancers. Accumulating evidence suggests that interfering with the PD-1-PD-L1 interaction may result in the restoration of defective T cell functions in cancer and chronic viral infection. Herein, we established procedures to produce large amounts of renatured recombinant extracellular domain proteins of mouse PD-1 (mPD-1) and PD-L1. While monomeric mPD-1 and mouse PD-L1 (mPD-L1) only marginally interacted with the cells expressing their counterpart proteins, their tetramerization markedly enhanced the affinity with the K(d) of mPD-L1 tetramer being nearly 100-fold lower than that of the corresponding monomer. The affinity of mPD-L1 tetramer was even higher than a high-affinity anti-PD-1 mAb, and it efficiently inhibited the binding of mPD-L1/Fc-chimeric protein to mPD-1(+) cells. Functionally, mPD-L1 tetramer significantly enhanced the proliferative responses as well as the cytotoxic activity of T cells against specific target cells in vitro. The results suggest that oligomeric PD-L1 extracellular domains may provide a potential means to restore T cell functions in cancer and viral infection in humans.