Download MendeleyStructural and Functional Basis for LILRB Immune Checkpoint Receptor Recognition of HLA-G Isoforms.
Kuroki, K., Matsubara, H., Kanda, R., Miyashita, N., Shiroishi, M., Fukunaga, Y., Kamishikiryo, J., Fukunaga, A., Fukuhara, H., Hirose, K., Hunt, J.S., Sugita, Y., Kita, S., Ose, T., Maenaka, K.(2019) J Immunol 203: 3386-3394
- PubMed: 31694909
- DOI: https://doi.org/10.4049/jimmunol.1900562
- Primary Citation of Related Structures:
6K60 - PubMed Abstract:
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 β2-microglobulin (β2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized β2m-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 α3 domain, but maintains tight contacts with β2m, thus accounting for β2m-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.
Organizational Affiliation:
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
