Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab

  • Nat Commun. 2024 Aug 29;15(1):7513. doi: 10.1038/s41467-024-51930-5.
Qianqian Ming  1 ,  Daniel Antfolk  1 ,  David A Price  2 ,  Anna Manturova  1 ,  Elliot Medina  1 ,  Srishti Singh  1 ,  Charlotte Mason  1 ,  Timothy H Tran  3 ,  Keiran S M Smalley  4 ,  Daisy W Leung  2 ,  Vincent C Luca  5
Affiliations
  • 1. Moffitt Cancer Center and Research Institute, Department of Immunology, Tampa, FL, 33612, USA.
  • 2. Washington University School of Medicine, Department of Medicine, St. Louis, MO, 63110, USA.
  • 3. Moffitt Cancer Center and Research Institute, Chemical Biology Core, Tampa, FL, 33612, USA.
  • 4. Moffitt Cancer Center and Research Institute, Department of Tumor Microenvironment and Metastasis, Tampa, FL, 33612, USA.
  • 5. Moffitt Cancer Center and Research Institute, Department of Immunology, Tampa, FL, 33612, USA. [email protected].
PMID: 39209860 DOI: 10.1038/s41467-024-51930-5
Abstract

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-Ab, revealing that domain 1 (D1) of LAG3 binds a conserved, membrane-proximal region of MHC-II spanning both the α2 and β2 subdomains. LAG3 dimerization restricts the intermolecular spacing of MHC-II molecules, which may attenuate T cell activation by enforcing suboptimal signaling geometry. The LAG3-MHC-II interface overlaps with the MHC-II-binding site of the T cell coreceptor CD4, implicating disruption of CD4-MHC-II interactions as a mechanism for LAG3 immunosuppressive function. Lastly, antibody epitope analysis indicates that multiple LAG3 inhibitors do not recognize the MHC-II-binding interface of LAG3, suggesting a role for functionally distinct mechanisms of LAG3 antagonism in therapeutic development.

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