HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8 - Agonist and antagonist profiles of viral chemokines
HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8 - Agonist and antagonist profiles of viral chemokines
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DOI：
10.1074/jbc.274.31.21569
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发表时间：
1999-07-30
影响因子：
4.8
通讯作者：
Schall, TJ
中科院分区：
文献类型：
--
作者：
Dairaghi, DJ;Fan, PA;Schall, TJ
关于病毒趋化因子功能的不确定性反映在对病毒编码的蛋白质使用宿主趋化因子受体的不完全了解上。一种这样的分子是vMIP-1，一种功能和结合特异性不确定的C-C型趋化因子，由卡波西肉瘤疱疹病毒HHV-8编码。我们在这里报告，vMIP-1结合并诱导细胞溶质[Ca 2 +]信号在人类T细胞中选择性地通过CCR 8，CC趋化因子受体与Th 2淋巴细胞。此外，使用一组65种不同的人类，病毒，和啮齿动物趋化因子，我们已经建立了一个强有力的配体结合“指纹”的CCR 8。该受体仅对四种趋化因子表现出显著的“高”亲和力（Kd < 15 nM），其中三种是病毒来源的：vMIP-1、vMIP-11、VMCC-1和人I-309。先前未报道的第二类较低亲和力配体包括MCP-3和可能的两种其他病毒趋化因子。vMIP-1和I-309似乎作为CCR 8激动剂：通过受体结合并诱导胞质[Ca 2 +]升高。相比之下，vMIP-II和vMCC-I作为有效的拮抗剂：结合而不诱导信号传导，并阻断I-309和vMIP-I的作用。这些结果表明CCR 8的配体层次结构，将vMIP-1鉴定为选择性的。因此，作为病毒趋化因子激动剂，CCR 8可以使趋化因子的特定亚群在病毒感染和免疫调节期间具有相互调节的潜力。
Uncertainty regarding viral chemokine function is mirrored by an incomplete knowledge of host chemokine receptor usage by the virally encoded proteins. One such molecule is vMIP-I, a C-C type chemokine of undefined function and binding specificity, encoded by the Kaposi's sarcoma herpesvirus HHV-8. We report here that vMIP-I binds to and induces cytosolic [Ca2+] signals in human T cells selectively through CCR8, a CC chemokine receptor associated with Th2 lymphocytes, Furthermore, using a panel of 65 different human, viral, and rodent chemokines, we have established a comprehen sive ligand binding "fingerprint" for CCR8. The receptor exhibits marked "high" affinity (K-d < 15 nM) only for four chemokines, three of them of viral origin: vMIP-I, vMIP-II, VMCC-I, and human I-309, A previously unreported second class of lower affinity ligands includes MCP-3 and possibly two other viral chemokines. vMIP-I and I-309 appear to act as CCR8 agonists: binding to and inducing cytosolic [Ca2+] elevation through the receptor. By contrast, vMIP-II and vMCC-I act as potent antagonists: binding without inducing signaling, and blocking the effects of I-309 and vMIP-I. These results suggest a ligand hierarchy for CCR8, identifying vMIP-I as a selective. viral chemokine agonist, CCR8 may thus engage a specific subset of chemokines with the potential to regulate each other during viral infection and immune regulation.