The chemokine CXCL10 is released by a plethora of cells, including immune and metastatic cancer cells, following stimulation with interferon-gamma. It acts via its GPC receptor on T-cells attracting them to various target tissues. Glycosaminoglycans (GAGs) are regarded as co-receptors of chemokines, which enable the establishment of a chemotactic gradient for target cell migration. We have engineered human CXCL10 towards improved T-cell mobilisation by implementing a single site-directed mutation N20K into the protein, which leads to a higher GAG binding affinity compared to the wild type. Interestingly, this mutation not only increased T-cell migration in a transendothelial migration assay, the mutant intensified T-cell chemotaxis also in a Boyden chamber set-up thereby indicating a strong role of T-cell-localised GAGs on leukocyte migration. A CXCL10 mutant with increased GAG-binding affinity could therefore potentially serve as a T-cell mobiliser in pathological conditions where the immune surveillance of the target tissue is impaired, as is the case for most solid tumors.

中文翻译：

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通过增强的GAG结合亲和力设计一种改进的T细胞动员CXCL10突变体。

干扰素-γ刺激后，趋化因子CXCL10由多种细胞释放，包括免疫和转移性癌细胞。它通过其GPC受体作用于T细胞，将其吸引至各种靶组织。糖胺聚糖（GAGs）被认为是趋化因子的共受体，可为靶细胞迁移建立趋化梯度。我们已经通过将单个定点突变N20K导入蛋白质中，对人CXCL10进行了工程改造，以提高T细胞的动员能力，与野生型相比，这导致了更高的GAG结合亲和力。有趣的是，该突变不仅增加了跨内皮迁移测定中的T细胞迁移，而且突变体还在Boyden腔室设置中增强了T细胞趋化性，从而表明T细胞定位的GAG对白细胞迁移具有很强的作用。