美国圣犹大儿童研究医院Dario A. A. Vignali、Creg J. Workman等研究人员合作发现，LAG3与T细胞受体（TCR）-CD3复合物结合并通过驱动共受体-Lck解离来抑制信号传导。这一研究成果于2022年4月18日在线发表在国际学术期刊《自然—免疫学》上。

研究人员发现，LAG3移动到免疫突触，并与CD4⁺和CD8⁺ T细胞中的TCR-CD3复合物结合，而不与主要组织相容性复合物II类（其经典配体）结合。从机制上讲，LAG3细胞质尾部的一个系统发育保守的酸性串联谷氨酸-脯氨酸重复降低了免疫突触的pH值，导致酪氨酸激酶Lck与CD4或CD8共同受体分离，从而导致共同受体-TCR信号的丧失和有限的T细胞激活。这些观察表明，LAG3以独立于主要组织相容性复合体II类的方式发挥信号破坏者的功能，并为LAG3靶向免疫疗法的作用机制提供了启示。

据介绍，LAG3是一种抑制性受体，在衰竭的T细胞上高度表达。尽管针对LAG3的免疫治疗药物目前正在进行临床试验，但LAG3如何抑制T细胞功能仍不清楚。

附：英文原文

Title: LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation

Author: Guy, Clifford, Mitrea, Diana M., Chou, Po-Chien, Temirov, Jamshid, Vignali, Kate M., Liu, Xueyan, Zhang, Hui, Kriwacki, Richard, Bruchez, Marcel P., Watkins, Simon C., Workman, Creg J., Vignali, Dario A. A.

Issue&Volume: 2022-04-18

Abstract: LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4+ and CD8+ T cells, in the absence of binding to major histocompatibility complex classII—its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid–proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor–TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in a major histocompatibility complex classII-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.

DOI: 10.1038/s41590-022-01176-4

Source: https://www.nature.com/articles/s41590-022-01176-4