Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY.
La Jolla Institute for Immunology, La Jolla, CA.
J Exp Med. 2021 Dec 6;218(12). doi: 10.1084/jem.20211112. Epub 2021 Oct 28.
HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM-LIGHT-CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
HVEM 是一种 TNF（肿瘤坏死因子）受体，参与涉及多种细胞类型的广泛免疫功能。它与 TNF 配体 LIGHT 以及免疫球蛋白 (Ig) 超家族成员 BTLA 和 CD160 相互作用。在不同环境下评估 HVEM 与特定配体结合的功能影响，由于 HVEM 和 HVEM 结合伙伴的多种相互作用而变得复杂。为了剖析多种功能的分子基础，我们确定了晶体结构，揭示了 HVEM 与 LIGHT 或 BTLA/CD160 结合的不同表面，包括人 HVEM-LIGHT-CD160 三元复合物，其中 HVEM 同时与两个结合伙伴相互作用。基于这些结构，我们生成了体外选择性识别 TNF 或 Ig 配体的小鼠 HVEM 突变体。表达这些突变体的基因敲入小鼠保留了 HVEM 网络中所有蛋白质的表达，但它们在清除肠道细菌方面表现出 LIGHT 的选择性功能，在改善肝脏炎症方面表现出 Ig 配体的选择性功能。
