Molecular Basis for Herpesvirus Entry Mediator Recognition by the Human Immune Inhibitory Receptor CD160 and Its Relationship to the Cosignaling Molecules BTLA and LIGHT
Molecular Basis for Herpesvirus Entry Mediator Recognition by the Human Immune Inhibitory Receptor CD160 and Its Relationship to the Cosignaling Molecules BTLA and LIGHT
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DOI：
10.1016/j.jmb.2011.09.018
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发表时间：
2011-11-04
影响因子：
5.6
通讯作者：
Maenaka, Katsumi
中科院分区：
文献类型：
--
作者：
Kojima, Rieko;Kajikawa, Mizuho;Maenaka, Katsumi
CD160是最近发现的一种T细胞共抑制分子，它与抗原提呈细胞上的疱疹病毒进入介体(HSEM)相互作用，向CD4(+)T细胞传递强大的抑制信号。HVEM还与共抑制受体BTLA(B淋巴细胞和T淋巴细胞衰减器)和共刺激受体LIGH(与淋巴毒素同源，具有诱导性表达，并与单纯疱疹病毒糖蛋白D竞争由T淋巴细胞表达的受体HVEM，或TNFSF14)，从而调节CD160/BTLA/LIGT/HVEM信号通路。到目前为止，这些复合体形成的详细性质，特别是与新发现的受体CD160的结合，以及CD160与BTLA和LIGH的关系仍不清楚。我们进行了N-末端测序和质谱分析，结果表明CD160的胞外区主要以单体形式存在。表面等离子体共振分析表明，CD160直接与hVEM富含半胱氨酸的结构域1-3结合，亲和力与BTLA相似，但解离速度慢于BTLA。值得注意的是，CD160与BTLA竞争与HVEM的结合；相反，光不影响HVEM与CD160或BTLA的结合。HVEM的诱变研究结果还表明，HVEM上的CD160结合区与BTLA结合部位略有不同，但有重叠。有趣的是，一种具有抗血管生成特性的抗CD160抗体阻断了CD160/HVEM的结合。这些结果为我们深入了解CD160/BTLA/LIGHT/HVEM信号复合体调节免疫功能的分子结构提供了线索。(C)2011爱思唯尔有限公司。保留所有权利。
CD160 was recently identified as a T cell coinhibitory molecule that interacts with the herpesvirus entry mediator (HVEM) on antigen-presenting cells to deliver a potent inhibitory signal to CD4(+) T cells. HVEM also binds to the coinhibitory receptor BTLA (B- and T-lymphocyte attenuator) and the costimulatory receptor LIGHT (which is homologous to lymphotoxins, exhibits inducible expression, and competes with the herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14), thus regulating the CD160/BTLA/LIGHT/HVEM signaling pathway. To date, the detailed properties of the formation of these complexes, especially HVEM binding to the newly identified receptor CD160, and the relationship of CD160 with BTLA and LIGHT are still unclear. We performed N-terminal sequencing and a mass spectrometric analysis, which revealed that the extracellular domain of CD160 exists primarily in the monomeric form. The surface plasmon resonance analysis revealed that CD160 binds directly to the cysteine-rich domain 1-3 of HVEM with a similar affinity to, but slower dissociation rate than, that of BTLA. Notably, CD160 competed with BTLA for binding to HVEM; in contrast, LIGHT did not affect HVEM binding to either CD160 or BTLA. The results of a mutagenesis study of HVEM also suggest that the CD160 binding region on HVEM was slightly different from, but overlapped with, the BTLA binding site. Interestingly, an anti-CD160 antibody exhibiting antiangiogenic properties blocked CD160/HVEM binding. These results provide insight into the molecular architecture of the CD160/BTLA/LIGHT/HVEM signaling complex that regulates immune function. (C) 2011 Elsevier Ltd. All rights reserved.