T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.
T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment.
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DOI：
10.4049/jimmunol.0902490
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Ware CF
中科院分区：
文献类型：
--
作者：
Cheung TC;Oborne LM;Steinberg MW;Macauley MG;Fukuyama S;Sanjo H;D'Souza C;Norris PS;Pfeffer K;Murphy KM;Kronenberg M;Spear PG;Ware CF
在TNF受体疱疹病毒进入介体（HVEM，TNFRSF 14）和IG超家族成员B和T淋巴细胞衰减剂（BTLA）和CD 160之间形成的抑制性共信号传导途径限制了T细胞的活化。然而，BTLA和CD 160也可以作为激活配体HVEM时，在反式提出的相邻细胞，从而形成一个双向信号传导途径。BTLA和CD 160可以直接激活HREM依赖性NF-κB RelA转录复合物，这提出了在初始T细胞中NF-κB激活如何被抑制的问题。在这项研究中，我们发现BTLA与HVEM顺式相互作用，在初始T细胞中形成异二聚体复合物，抑制HVEM依赖的NF-κB活化。HVEM和BTLA之间的顺式相互作用是在初始人和小鼠T细胞表面上表达的主要形式。BTLA胞外域作为竞争性抑制剂，阻断BTLA和CD 160与HVEM反式结合并启动NF-κB活化。TNF-相关配体LIGHT（与光敏素同源，表现出可诱导表达，并与HSV糖蛋白D竞争HVEM（T淋巴细胞表达的受体）或TNFSF 14）结合顺式复合物中的HVEM，但NF-κB活化减弱，表明BTLA阻止了顺式复合物中HVEM的寡聚化。BTLA的遗传缺失或HVEM-BTLA顺式复合物在T细胞中的药理学破坏促进HVEM的反式激活。有趣的是，单纯疱疹病毒包膜糖蛋白D与HVEM形成顺式复合物，但令人惊讶的是，促进NF-κB RelA的激活。我们认为HVEM-BTLA顺式复合物通过周围微环境中表达的配体竞争性抑制HVEM活化，从而帮助维持T细胞处于幼稚状态。
The inhibitory cosignaling pathway formed between the TNF receptor herpesvirus entry mediator (HVEM, TNFRSF14) and the Ig superfamily members, B and T lymphocyte attenuator (BTLA) and CD160, limits the activation of T cells. However, BTLA and CD160 can also serve as activating ligands for HVEM when presented in trans by adjacent cells, thus forming a bidirectional signaling pathway. BTLA and CD160 can directly activate the HVEM-dependent NF-κB RelA transcriptional complex raising the question of how NF-κB activation is repressed in naive T cells. In this study, we show BTLA interacts with HVEM in cis, forming a heterodimeric complex in naive T cells that inhibits HVEM-dependent NF-κB activation. The cis-interaction between HVEM and BTLA is the predominant form expressed on the surface of naive human and mouse T cells. The BTLA ectodomain acts as a competitive inhibitor blocking BTLA and CD160 from binding in trans to HVEM and initiating NF-κB activation. The TNF-related ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes, or TNFSF14) binds HVEM in the cis-complex, but NF-κB activation was attenuated, suggesting BTLA prevents oligomerization of HVEM in the cis-complex. Genetic deletion of BTLA or pharmacologic disruption of the HVEM-BTLA cis-complex in T cells promoted HVEM activation in trans. Interestingly, herpes simplex virus envelope glycoprotein D formed a cis-complex with HVEM, yet surprisingly, promoted the activation NF-κB RelA. We suggest that the HVEM-BTLA cis-complex competitively inhibits HVEM activation by ligands expressed in the surrounding microenvironment, thus helping maintain T cells in the naive state.
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DOI：
10.1084/jem.20071160
发表时间：
2008-06-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Steinberg MW;Turovskaya O;Shaikh RB;Kim G;McCole DF;Pfeffer K;Murphy KM;Ware CF;Kronenberg M
通讯作者：
Kronenberg M
DOI：
10.1073/pnas.0902115106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Cheung, Timothy C.;Steinberg, Marcos W.;Ware, Carl F.
通讯作者：
Ware, Carl F.
影响因子：
32.4
作者：
Kabashima, K;Banks, TA;Cyster, JG
通讯作者：
Cyster, JG
影响因子：
4.4
作者：
Nelson, Christopher A.;Fremont, Marcel D.;Fremont, Daved H.
通讯作者：
Fremont, Daved H.
影响因子：
4.4
作者：
De Trez, Carl;Schneider, Kirsten;Ware, Carl F.
通讯作者：
Ware, Carl F.