Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors

Kiave Yune HoWangYin, Maria Loustau, Juan Wu, Estibaliz Alegre, Marina Daouya, Julien Caumartin, Sylvie Sousa, Anatolij Horuzsko, Edgardo D. Carosella, Joel LeMaoult

Research output: Contribution to journalArticle

36 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)4041-4049
Number of pages9
JournalCellular and Molecular Life Sciences
Volume69
Issue number23
DOIs
StatePublished - Dec 1 2012

Keywords

  • HLA-G
  • Immune regulation
  • Inhibitory receptors
  • Transplantation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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    HoWangYin, K. Y., Loustau, M., Wu, J., Alegre, E., Daouya, M., Caumartin, J., Sousa, S., Horuzsko, A., Carosella, E. D., & LeMaoult, J. (2012). Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors. Cellular and Molecular Life Sciences, 69(23), 4041-4049. https://doi.org/10.1007/s00018-012-1069-3