Abstract
The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α1–α2–α3 non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α1–α3 structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α1–α3-Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents.
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Acknowledgments
We thank Mr. Romain Crolas, Mr. Jeremy Baudhuin, and Dr. Benoit Favier for their technical help in this project. This work was supported by Commissariat a l’Energie Atomique et aux Energies Alternatives, in part by HLA-G Technologies (to A.H.), and by National Institute of Health grant R56 AI055923 (to A. H.).
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Supplementary material Phenotype of the NKL-LILRB1+ and NKL-LILRB1+LILRB2+ cells.Cytometry analysis of the cell-surface expression of LILRB1 and LILRB2 receptors on NKLLILRB1+ and NKL-LILRB1+LILRB2+ cells 3 (PPTX 100 kb)
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HoWangYin, KY., Loustau, M., Wu, J. et al. Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors. Cell. Mol. Life Sci. 69, 4041–4049 (2012). https://doi.org/10.1007/s00018-012-1069-3
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DOI: https://doi.org/10.1007/s00018-012-1069-3