Moffitt Cancer Center and Research Institute, Department of Immunology, Tampa, FL, 33612, USA.
Washington University School of Medicine, Department of Medicine, St. Louis, MO, 63110, USA.
Nat Commun. 2024 Aug 29;15(1):7513. doi: 10.1038/s41467-024-51930-5.
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-A, 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.
免疫检查点蛋白，淋巴细胞激活基因-3（LAG3），与主要组织相容性复合体 II（MHC-II）结合并抑制 T 细胞激活。尽管最近 FDA 批准了一种 LAG3 抑制剂用于治疗黑色素瘤，但 LAG3 如何在细胞表面与 MHC-II 结合仍知之甚少。在这里，我们确定了与 MHC-II 分子 I-A 结合的小鼠 LAG3 的 3.84 Å 分辨率结构，揭示了 LAG3 的结构域 1（D1）结合 MHC-II 的一个保守的、位于膜附近的区域，跨越α2 和β2 亚结构域。LAG3 二聚化限制了 MHC-II 分子的分子间间距，这可能通过强制非最佳信号几何形状来减弱 T 细胞激活。LAG3-MHC-II 界面与 T 细胞共受体 CD4 的 MHC-II 结合位点重叠，暗示破坏 CD4-MHC-II 相互作用是 LAG3 免疫抑制功能的一种机制。最后，抗体表位分析表明，多种 LAG3 抑制剂不能识别 LAG3 的 MHC-II 结合界面，这表明在治疗性开发中 LAG3 拮抗作用的功能不同机制可能起作用。
