Oligomerization of CXCL10 is necessary for endothelial cell presentation and in vivo activity
Oligomerization of CXCL10 is necessary for endothelial cell presentation and in vivo activity
复制标题
DOI：
10.4049/jimmunol.177.10.6991
复制
发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Luster, Andrew D.
中科院分区：
文献类型：
--
作者：
Campanella, Gabriele S. V.;Grimm, Jan;Luster, Andrew D.
10 kDa 的趋化因子 IFN-γ 诱导蛋白（IP-10；CXCL10）通过与 G 蛋白偶联受体 CXCR3 相互作用，在将活化的 T 淋巴细胞募集到炎症部位中发挥重要作用。 IP-10 与其他趋化因子一样，形成寡聚体，其作用尚未被探索。在本研究中，我们使用单体 IP-10 突变体来阐明寡聚化的功能意义。尽管单体 IP-10 对 CXCR3 和肝素的结合亲和力降低，但它能够诱导活化 T 细胞的体外趋化性，其功效与野生型 IP-10 相同。然而，气管内滴注后，单体IP-10无法诱导活化的CD8+T细胞募集到小鼠气道中。使用不同的 IP-10 突变体证明这种无能力是由于缺乏寡聚化而不是 CXCR3 或肝素结合减少。分子成像表明，气管内滴注后，野生型和单体IP-10均保留在肺部。然而，体外结合测定表明野生型（而非单体）IP-10 保留在内皮细胞上，并且可以诱导活化 T 细胞的跨内皮趋化性。因此，我们提出，内皮细胞上的呈递和随后的跨内皮迁移需要 IP-10 的寡聚化，这是体内淋巴细胞募集的重要步骤。
The chemokine IFN-gamma-inducible protein of 10 kDa (IP-10; CXCL10) plays an important role in the recruitment of activated T lymphocytes into sites of inflammation by interacting with the G protein-coupled receptor CXCR3. IP-10, like other chemokines, forms oligomers, the role of which has not yet been explored. In this study, we used a monomeric IP-10 mutant to elucidate the functional significance of oligomerization. Although monomeric IP-10 had reduced binding affinity for CXCR3 and heparin, it was able to induce in vitro chemotaxis of activated T cells with the same efficacy as wild-type IP-10. However, monomeric IP-10 was unable to induce recruitment of activated CD8(+) T cells into the airways of mice after intratracheal instillation. Use of a different IP-10 mutant demonstrated that this inability was due to lack of oligomerization rather than reduced CXCR3 or heparin binding. Molecular imaging demonstrated that both wild-type and monomeric IP-10 were retained in the lung after intratracheal instillation. However, in vitro binding assays indicated that wild-type, but not monomeric, IP-10 was retained on endothelial cells and could induce transendothelial chemotaxis of activated T cells. We therefore propose that oligomerization of IP-10 is required for presentation on endothelial cells and subsequent transendothelial migration, an essential step for lymphocyte recruitment in vivo.