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

Area of Science:

• Immunology
• Transplantation Biology
• Molecular Biology

Background:

• Human Leukocyte Antigen G (HLA-G) is a non-classical MHC class I molecule with unique characteristics including low genetic diversity, tissue-restricted expression, multiple isoforms, and potent immuno-inhibitory functions.
• Known functions primarily involve membrane-bound HLA-G1 and soluble HLA-G5, which possess a classical HLA class I structure (heavy chain non-covalently bound to β-2-microglobulin and peptide).
• Limited knowledge exists regarding the structural features and functions of other HLA-G isoforms and non-classical structural conformations.

Purpose of the Study:

• To investigate the capability of all HLA-G isoforms to form homomultimers.
• To determine if HLA-G isoforms can bind to and function through the known HLA-G receptors, LILRB1 and LILRB2.
• To explore the potential of truncated HLA-G isoforms as therapeutic agents.

Main Methods:

• Studied homomultimerization of all known HLA-G isoforms.
• Investigated binding interactions between HLA-G isoforms and LILRB1/LILRB2 receptors.
• Utilized α1-α3-Fc structures coated on agarose beads to assess tolerogenic properties and in vivo efficacy in mouse models.

Main Results:

• All HLA-G isoforms demonstrated the ability to form homodimers, including the novel identification of HLA-G4 dimers.
• The extracellular α1-α3 structure of HLA-G2 and HLA-G6 was found to bind LILRB2 but not LILRB1, representing the first identified receptor for a truncated HLA-G isoform.
• The α1-α3-Fc structure exhibited tolerogenic properties, significantly prolonging skin allograft survival in B6 mice and a LILRB2-transgenic mouse model.

Conclusions:

• This study provides the first evidence that all HLA-G isoforms can form homodimers.
• A novel interaction between truncated HLA-G isoforms (via their α1-α3 domains) and the LILRB2 receptor was discovered.
• Truncated HLA-G isoforms show therapeutic potential, demonstrating a proof-of-concept for their use in prolonging allograft survival.