Structural basis for mouse LAG3 interactions with the MHC class II molecule I-A^b

Area of Science:

• Immunology
• Structural Biology
• Cancer Research

Background:

• Lymphocyte-activation gene-3 (LAG3) is an immune checkpoint protein that binds Major Histocompatibility Complex Class II (MHC-II) to inhibit T cell responses.
• LAG3 inhibitors are approved for melanoma treatment, but the structural basis of LAG3-MHC-II interaction is not fully understood.
• Understanding this interaction is crucial for developing novel cancer immunotherapies.

Purpose of the Study:

• To determine the high-resolution structure of the mouse LAG3 protein bound to the MHC-II molecule I-A^b.
• To elucidate the molecular mechanisms by which LAG3 binding to MHC-II suppresses T cell activation.
• To investigate the implications for therapeutic strategies targeting the LAG3-MHC-II pathway.

Main Methods:

• X-ray crystallography to determine the 3.84 Å-resolution structure of the LAG3-MHC-II complex.
• Analysis of the protein-protein interface to identify key binding residues and interactions.
• Antibody epitope mapping to assess the binding sites of existing LAG3 inhibitors.

Main Results:

• The structure reveals that domain 1 of LAG3 binds to a conserved region of MHC-II, spanning both α2 and β2 subdomains.
• LAG3 dimerization induces specific spacing between MHC-II molecules, potentially leading to suboptimal T cell receptor signaling.
• The LAG3-MHC-II binding interface overlaps with the binding site for the T cell coreceptor CD4, suggesting interference with CD4-MHC-II interactions.
• Existing LAG3 inhibitors were found not to target the MHC-II binding interface of LAG3.

Conclusions:

• The structural insights provide a detailed understanding of how LAG3 engages MHC-II on the cell surface.
• LAG3-mediated suppression of T cell activation may occur through disruption of CD4-MHC-II interactions and altered MHC-II clustering.
• The distinct binding sites of current inhibitors suggest diverse mechanisms for LAG3 antagonism, opening avenues for next-generation therapeutics.