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, Vincent C. Luca
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. Lymphocyte activation gene-3 (LAG3) is an immune checkpoint protein recently approved as a target for anti-melanoma therapy. Here, the authors solve the structure of mouse LAG3 bound to MHC-II to show that LAG3 blocks MHC-II/CD4 interactions, thereby implicating a potential mechanism of LAG3-mediated immune suppression.