Cutting Edge: LAG3 Dimerization Is Required for TCR/CD3 Interaction and Inhibition of Antitumor Immunity.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Kieran Adam, Zhanna Lipatova, Maria Abdul Ghafoor Raja, Arjun K Mishra, Roy A Mariuzza, Creg J Workman, Dario A A Vignali
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引用次数: 0

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.

前沿:LAG3 二聚化是 TCR/CD3 相互作用和抑制抗肿瘤免疫所必需的。
淋巴细胞活化基因 3(LAG3)是一种抑制性受体,在控制 T 细胞耐受性和自身免疫方面起着关键作用,是主要的免疫治疗靶点。LAG3 以同源二聚体的形式在细胞表面表达,但其功能相关性尚不清楚。在这项研究中,我们发现在 CD8+ T 细胞中,TCR/CD3 复合物与不能二聚的小鼠 LAG3 突变体之间的关联受到了干扰。我们还证明,在 B16-gp100 肿瘤模型中,LAG3 二聚化是发挥最佳抑制功能的必要条件。最后,我们证明了一种治疗性 LAG3 抗体 C9B7W 不会阻断 LAG3 与其同源配体 MHC class II 的相互作用,但会破坏 LAG3 的二聚化及其与 TCR/CD3 复合物的结合。这些研究强调了 LAG3 二聚化的功能重要性,并提供了更多针对 LAG3 的治疗方法。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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