纽约大学王俊研究组提出了LAG-3和T细胞受体之间的接近指导T细胞活化和自身免疫的抑制。相关论文于2025年6月30日发表在《细胞》杂志上。
虽然已知活化T细胞上特异性表达的抑制检查点受体LAG-3与主要组织相容性复合体II类（MHC II类）结合，但研究人员证明仅MHC II类相互作用不足以实现最佳LAG-3功能。相反，LAG-3在同源肽-MHC II类的促进下，与T细胞受体（TCR）而不是CD4共受体的空间接近，在介导CD4+ T细胞抑制中是至关重要的。从机制上讲，LAG-3通过其细胞内FSAL基序与TCR信号成分CD3ε形成凝聚，破坏CD3ε/淋巴细胞特异性蛋白激酶（Lck）的结合。为了利用LAG-3与TCR的接近性并最大限度地抑制LAG-3依赖性T细胞，该课题组研究人员开发了一种Fc减毒的LAG-3/TCR抑制双特异性抗体，以绕过同源肽-MHC II类的要求。这种方法可以有效地抑制CD4+和CD8+ T细胞，并有效地缓解motheme模型中的自身免疫症状。他们的发现揭示了一种复杂的、有条件的检查点调节机制，并强调了LAG-3/TCR顺式邻近靶向治疗缺乏有效和耐受性良好的免疫疗法的T细胞驱动的自身免疫性疾病。
据介绍，在自身免疫性疾病中靶向致病性T细胞的治疗一直具有挑战性。
附：英文原文
Title: Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity
Author: Jasper Du, Hui Chen, Jia You, Wei Hu, Jia Liu, Qiao Lu, Yong Zhang, Jie Gao, Meng-ju Lin, Connor James Ryan Foster, Eric Rao, Michael Cammer, Weiwei Yin, Shohei Koide, Catherine Pei-ju Lu, Wei Chen, Jizhong Lou, Jun Wang
Issue&Volume: 2025-06-30
Abstract: Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3’s spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3’s proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.
DOI: 10.1016/j.cell.2025.06.004
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00638-5