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

Qianqian Ming, Daniel Antfolk, David A. Price, Anna Manturova, Elliot Medina, Srishti Singh, Charlotte Mason, Timothy H. Tran, Keiran S. M. Smalley, Daisy W. Leung and Vincent C. Luca ()
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Qianqian Ming: Department of Immunology
Daniel Antfolk: Department of Immunology
David A. Price: Department of Medicine
Anna Manturova: Department of Immunology
Elliot Medina: Department of Immunology
Srishti Singh: Department of Immunology
Charlotte Mason: Department of Immunology
Timothy H. Tran: Chemical Biology Core
Keiran S. M. Smalley: Department of Tumor Microenvironment and Metastasis
Daisy W. Leung: Department of Medicine
Vincent C. Luca: Department of Immunology

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51930-5

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