Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway
Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway
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DOI：
10.1073/pnas.0506172102
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发表时间：
2005-09-13
影响因子：
11.1
通讯作者：
Ware, CF
中科院分区：
文献类型：
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作者：
Cheung, TC;Humphreys, IR;Ware, CF
疱疹病毒进入介体（HVEM）是TNF受体（TNFR）超家族的成员，其可作为分子开关，通过传播来自TNF相关配体LIGHT（TNFR超家族14）的阳性信号或通过超家族成员IG B和T淋巴细胞衰减剂（BTLA）的抑制信号来调节T细胞活化。竞争结合分析和诱变揭示了一个独特的BTLA结合位点集中在一个关键的赖氨酸残基在半胱氨酸丰富的结构域1的HVEM。HVEM上的BTLA结合位点与单纯疱疹病毒1包膜糖蛋白D的结合位点重叠，但与LIGHT结合的位点不同，但糖蛋白D抑制两种配体的结合，可能使该途径无效。HVEM上BTLA的结合位点在人CMV中存在的孤儿TNFR UL 144中是保守的。UL 144结合BTLA，但不结合LIGHT，并抑制T细胞增殖，选择性地模拟HVEM的抑制性共信号功能。不同的疱疹病毒靶向HVEM-BTLA共信号通路的证明表明该通路在宿主防御期间调节T细胞活化的重要性。
The herpesvirus entry mediator (HVEM), a member of the TNF receptor (TNFR) superfamily, can act as a molecular switch that modulates T cell activation by propagating positive signals from the TNF-related ligand LIGHT (TNFR superfamily 14), or inhibitory signals through the Ig superfarnily member B and T lymphocyte attenuator (BTLA). Competitive binding analysis and mutagenesis reveals a unique BTLA binding site centered on a critical lysine residue in cysteine-rich domain 1 of HVEM. The BTLA binding site on HVEM overlaps with the binding site for the herpes simplex virus 1 envelope glycoprotein D, but is distinct from where LIGHT binds, yet glycoprotein D inhibits the binding of both ligands, potentially nullifying the pathway. The binding site on HVEM for BTLA is conserved in the orphan TNFR, UL144, present in human CMV. UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM. The demonstration that distinct herpesviruses target the HVEM-BTLA cosignaling pathway suggests the importance of this pathway in regulating T cell activation during host defenses.