Structural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms
Structural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms
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DOI：
10.4049/jimmunol.1900562
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发表时间：
2019-12-15
影响因子：
4.4
通讯作者：
Maenaka, Katsumi
中科院分区：
文献类型：
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作者：
Kuroki, Kimiko;Matsubara, Haruki;Maenaka, Katsumi
人类白细胞免疫球蛋白样受体(LILR)LILRB1和LilrB2是免疫检查点受体，通过与包括HLA-G在内的多种配体结合来调节广泛的生理反应。人类白细胞抗原-G仅在胎盘、一些免疫调节细胞和肿瘤中表达，并有几种独特的亚型。然而，LILRs对人类白细胞抗原G亚型的识别知之甚少。在这项研究中，我们研究了LILR与胎盘滋养层细胞合成的无β2-微球蛋白(β2M)的HLA-G1亚型的结合，这种亚型倾向于二聚化和多聚化。多聚化的不含2M的HLA-G1二聚体缺乏与LILRB1的亲和力，但与LilrB2强烈结合。我们还测定了LILRB1和人类白细胞抗原-G1复合体的晶体结构，它采用了经典的人类白细胞抗原I类复合体的典型结构。LILRB1与α3结构域表现出灵活的结合模式，但与β2M保持紧密接触，因此解释了β2M依赖的结合。值得注意的是，LILRB1和B2都以合适的角度定向，以允许在与HLA-G1二聚体形成复杂的信号时有效地传递信号。LILRs识别配体的这些结构和功能特征为了解它们在生物调节中的重要作用提供了新的见解。
Human leukocyte Ig-like receptors (LILR) LILRB1 and LILRB2 are immune checkpoint receptors that regulate a wide range of physiological responses by binding to diverse ligands, including HLA-G. HLA-G is exclusively expressed in the placenta, some immunoregulatory cells, and tumors and has several unique isoforms. However, the recognition of HLA-G isoforms by LILRs is poorly understood. In this study, we characterized LILR binding to the beta 2-microglobulin (beta 2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized beta 2m-free HLA-G1 dimer lacked detectable affinity for LILRB1, but bound strongly to LILRB2. We also determined the crystal structure of the LILRB1 and HLA-G1 complex, which adopted the typical structure of a classical HLA class I complex. LILRB1 exhibits flexible binding modes with the alpha 3 domain, but maintains tight contacts with beta 2m, thus accounting for beta 2m-dependent binding. Notably, both LILRB1 and B2 are oriented at suitable angles to permit efficient signaling upon complex formation with HLA-G1 dimers. These structural and functional features of ligand recognition by LILRs provide novel insights into their important roles in the biological regulations.