LAG3-MHCII interaction induces a tight cell-cell interface at the immunological synapse

作者：Zibin Wang, Ting Zhou, Hanbing Wang, He Li, Wene Zhao, Feng Wang, Yan Li, Wen Liu, Jia Wei, Xianchi Dong · 发表于：The Journal of Immunology · 年份：2025 · DOI：10.1093/jimmun/vkaf120 · 被引用次数：6 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

Lymphocyte activation gene 3 (LAG3), an immune checkpoint, inhibits T cell function by binding to major histocompatibility complex class II (MHCII). Although LAG3 holds significant therapeutic potential for cancer immunotherapy, the molecular mechanisms underlying LAG3-mediated immunosuppression remain poorly characterized. Here, using a reconstituted cell conjugation assay, we demonstrate that LAG3 binds directly to MHCII in a T cell receptor signaling-independent manner. Beyond its role in modulating intercellular adhesion, the LAG3-MHCII interaction remodels the architecture of the immunological synapse (IS). Correlative light and electron microscopy reveals that the LAG3-MHCII interaction creates a remarkably tight cell-cell interface at the IS, which selectively excludes CD4, large receptor-ligand complexes, and whole IgG of LAG3 antibodies. Conversely, the Fab fragment of LAG3 antibodies can penetrate this tight interface, block LAG3-MHCII binding, and enhance T cell responses. In addition, the LAG3-MHCII interaction directly facilitates MHCII trogocytosis. These findings demonstrate that the LAG3-MHCII interaction establishes a selective physical barrier at the IS, providing novel mechanistic insights into LAG3-mediated immunosuppression and suggesting feasible strategies for the development of more effective immunotherapeutic drugs.