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Publication Abstract from PubMed

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 beta2-microglobulin (beta2m)-free HLA-G1 isoform, which is synthesized by placental trophoblast cells and tends to dimerize and multimerize. The multimerized beta2m-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 alpha3 domain, but maintains tight contacts with beta2m, thus accounting for beta2m-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.

Structural 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 JS, Sugita Y, Kita S, Ose T, Maenaka K J Immunol. 2019 Nov 6. pii: jimmunol.1900562. doi: 10.4049/jimmunol.1900562. PMID:31694909^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.