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 class II—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 class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.

LAG3 是一种抑制性受体，在耗尽的 T 细胞上高度表达。尽管 LAG3 靶向免疫治疗目前处于临床试验阶段，但 LAG3 如何抑制 T 细胞功能仍不清楚。在这里，我们显示 LAG3 移动到免疫突触并与 CD4 ⁺和 CD8 ^{+中的 T 细胞受体 (TCR)-CD3 复合物相关}T 细胞，在没有与主要组织相容性复合物 II 类（其典型配体）结合的情况下。从机制上讲，LAG3 细胞质尾部中的系统发育保守、酸性、串联谷氨酸-脯氨酸重复序列降低了免疫突触的 pH 值，并导致酪氨酸激酶 Lck 从 CD4 或 CD8 共受体解离，从而导致 co 丢失。 -受体-TCR 信号传导和有限的 T 细胞活化。这些观察结果表明，LAG3 在主要组织相容性复合物 II 类非依赖性方式中作为信号干扰物发挥作用，并提供了对 LAG3 靶向免疫疗法的作用机制的深入了解。