LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition

Area of Science:

• Immunology
• Structural Biology
• Drug Development

Background:

• Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor that inhibits T cell function.
• LAG3 interacts with major histocompatibility complex class II (MHC class II) and fibrinogen-like protein 1 (FGL1).
• LAG3 is a promising target for next-generation immunotherapies, but its molecular structure and ligand interactions are poorly understood.

Purpose of the Study:

• To determine the molecular structure of human and murine LAG3 ectodomains.
• To elucidate the interaction mechanisms between LAG3 and its ligands (MHC class II and FGL1).
• To provide insights for the development of LAG3-based therapeutics.

Main Methods:

• X-ray crystallography to determine LAG3 ectodomain structures.
• Epitope mapping to identify antibody binding sites and their effect on ligand interactions.
• Mutational analysis to define the LAG3-FGL1 interface.
• Structural analysis of LAG3 and FGL1.

Main Results:

• The structures revealed a dimeric assembly of LAG3 mediated by Ig domain 2.
• A LAG3 antagonist antibody blocks MHC class II and FGL1 interactions by binding to a flexible loop 2 region in LAG3 domain 1.
• The LAG3-FGL1 interface was defined, showing that FGL1 cross-linking induces higher-order LAG3 oligomers.
• Ligand-mediated LAG3 clustering is implicated in T cell activation disruption.

Conclusions:

• The determined structures provide a molecular basis for LAG3 function and its inhibition of T cell activation.
• These findings can guide the rational design of LAG3-based immunotherapies.
• Ligand-induced clustering of LAG3 represents a potential mechanism for modulating immune responses.