LAG-3与T细胞受体之间的接近指导T细胞激活和自身免疫的抑制
Jasper Du1, Hui Chen2, Jia You1
1Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; The Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
Cell
|July 1, 2025
概括
针对T细胞上的LAG-3受体是自身免疫性疾病治疗的关键. 新的双特异性抗体通过与T细胞受体结合来增强LAG-3的功能,有效抑制致病性T细胞.
科学领域:
- 免疫学
- 自身免疫性疾病
- T细胞生物学
背景情况:
- 在自身免疫性疾病中向致病性T细胞仍然是一个重要的治疗挑战.
- 抑制检查点受体LAG-3与MHCII类结合,但其确切的功能尚未完全理解.
研究的目的:
- 阐明LAG-3功能在T细胞抑制中的机制.
- 开发针对T细胞驱动的自身免疫疾病的新型免疫疗法.
主要方法:
- 研究了LAG-3,T细胞受体 (TCR) 和CD3ε之间的相互作用.
- 开发了一个Fc减弱的LAG-3/TCR抑制双特异抗体.
- 在自免疫疾病的临床前小鼠模型中评估治疗疗效.
主要成果:
- 对于抑制CD4+T细胞而言,LAG-3与TCR的相互作用至关重要,而不仅仅是MHCII类.
- 通过其细胞内FSAL动机,LAG-3破坏了CD3ε/ Lck的关联.
- 这种新型双特异性抗体有效抑制CD4+和CD8+T细胞,缓解自身免疫症状.
结论:
- 地方行动组的功能取决于其与TCR的空间距离.
- 针对LAG-3/TCR的cis-proximity为治疗自身免疫性疾病提供了一个有前途的策略.
- 这种方法为缺乏有效治疗的免疫疗法提供了潜在的新途径.
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