Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Tumor Microenvironment Center, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA.
J Immunol. 2024 Jul 1;213(1):7-13. doi: 10.4049/jimmunol.2300673.
Lymphocyte activation gene 3 (LAG3) is an inhibitory receptor that plays a critical role in controlling T cell tolerance and autoimmunity and is a major immunotherapeutic target. LAG3 is expressed on the cell surface as a homodimer but the functional relevance of this is unknown. In this study, we show that the association between the TCR/CD3 complex and a murine LAG3 mutant that cannot dimerize is perturbed in CD8+ T cells. We also show that LAG3 dimerization is required for optimal inhibitory function in a B16-gp100 tumor model. Finally, we demonstrate that a therapeutic LAG3 Ab, C9B7W, which does not block LAG3 interaction with its cognate ligand MHC class II, disrupts LAG3 dimerization and its association with the TCR/CD3 complex. These studies highlight the functional importance of LAG3 dimerization and offer additional approaches to therapeutically target LAG3.
淋巴细胞激活基因 3（LAG3）是一种抑制性受体，在控制 T 细胞耐受和自身免疫方面发挥着关键作用，是主要的免疫治疗靶点。LAG3 作为同源二聚体在细胞表面表达，但这种功能的相关性尚不清楚。在这项研究中，我们表明，TCR/CD3 复合物与不能二聚化的小鼠 LAG3 突变体之间的关联在 CD8+T 细胞中受到干扰。我们还表明，LAG3 二聚化对于 B16-gp100 肿瘤模型中的最佳抑制功能是必需的。最后，我们证明了一种治疗性 LAG3 Ab，C9B7W，它不阻断 LAG3 与其同源配体 MHC 类 II 的相互作用，破坏了 LAG3 二聚化及其与 TCR/CD3 复合物的关联。这些研究强调了 LAG3 二聚化的功能重要性，并提供了针对 LAG3 的治疗性靶向的额外方法。
