de Duve Institute, UCLouvain, 1200 Brussels, Belgium.
Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium.
Science. 2018 Nov 23;362(6417):952-956. doi: 10.1126/science.aau2909. Epub 2018 Oct 25.
Transforming growth factor-β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (T) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This finding reveals how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by T.
转化生长因子-β1（TGF-β1）是少数以潜伏形式产生的细胞因子之一，需要激活才能发挥其在发育、免疫和癌症方面的广泛作用。调节性 T 细胞（T）通过激活 GARP（糖蛋白 A 重复为主）呈递的潜伏 TGF-β1 来抑制近距离的免疫细胞，该 GARP 与整合素 αVβ8 结合在其表面。我们解决了 GARP：与稳定该复合物并阻止活性 TGF-β1 释放的抗体结合的潜伏 TGF-β1 的晶体结构。这一发现揭示了 GARP 如何利用一系列不寻常的相互作用，包括 TGF-β1 氨基末端的折叠互补，来伴侣和定向细胞因子与 αVβ8 的结合和激活。因此，这项工作进一步阐明了抗体介导的 TGF-β1 激活和 T 抑制免疫的阻断机制。
