PDF(Pubmed)
Abstract：
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.
摘要：
淋巴细胞活化基因3（LAG3）是一种抑制性受体，在控制T细胞耐受和自身免疫中起关键作用，是主要的免疫治疗靶标。LAG3作为同源二聚体在细胞表面上表达,但其功能相关性未知。在这项研究中,我们表明，TCR/CD3复合物和不能二聚化的鼠LAG3突变体之间的关联在CD8+T细胞中被扰乱。我们还表明，在B16-gp100肿瘤模型中，LAG3二聚化是最佳抑制功能所必需的。最后,我们证明了治疗性LAG3Ab，C9B7W,不阻断LAG3与其同源配体MHCII类的相互作用，破坏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，并提供了治疗靶向LAG3的其他方法。
