TY - JOUR
T1 - Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors
AU - HoWangYin, Kiave Yune
AU - Loustau, Maria
AU - Wu, Juan
AU - Alegre, Estibaliz
AU - Daouya, Marina
AU - Caumartin, Julien
AU - Sousa, Sylvie
AU - Horuzsko, Anatolij
AU - Carosella, Edgardo D.
AU - LeMaoult, Joel
N1 - Funding Information:
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.).
PY - 2012/12
Y1 - 2012/12
N2 - 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 a1-a2-a3 non-covalently bound to b-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 a1-a3 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 a1-a3-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.
AB - 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 a1-a2-a3 non-covalently bound to b-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 a1-a3 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 a1-a3-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.
KW - HLA-G
KW - Immune regulation
KW - Inhibitory receptors
KW - Transplantation
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U2 - 10.1007/s00018-012-1069-3
DO - 10.1007/s00018-012-1069-3
M3 - Article
C2 - 22802125
AN - SCOPUS:84869065865
SN - 1420-682X
VL - 69
SP - 4041
EP - 4049
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 23
ER -