淋巴细胞激活基因 3 (LAG3) 是一种抑制性免疫检查点受体，可抑制自身免疫和抗肿瘤反应，但其进化上保守的细胞质尾部缺乏经典的抑制基序。主要组织相容性复合体 II 类（MHC II 类）是一种已确定的 LAG3 配体，纤维蛋白原样蛋白 1 (FGL1)、淋巴结窦内皮细胞 C 型凝集素 (LSECtin) 和 Galectin-3 已被提议作为替代结合伴侣在 LAG3 功能中发挥重要作用。在这里，我们使用荧光人类T细胞报告系统来研究LAG3的功能。我们发现，与受体程序性细胞死亡蛋白1相比，LAG3在MHC II类分子存在的情况下减少了对T细胞受体刺激的反应。对缺失突变体的分析表明，LAG3胞质尾部的RRFSALE基序是LAG3 介导的抑制是必要且充分的。在该系统中，FGL1（而不是 LSECtin 或 Galectin-3）充当 LAG3 配体，微弱地诱导抑制。 LAG3 阻断抗体减弱了报告细胞中 LAG3 介导的抑制，并且即使在没有 LAG3 配体的情况下也增强了报告细胞的活化，这表明它们可能独立于其阻断作用而增强 T 细胞反应。

Lymphocyte activation gene 3 (LAG3) is an inhibitory immune checkpoint receptor that restrains autoimmune and antitumor responses, but its evolutionarily conserved cytoplasmic tail lacks classical inhibitory motifs. Major histocompatibility complex class II (MHC class II) is an established LAG3 ligand, and fibrinogen-like protein 1 (FGL1), lymph node sinusoidal endothelial cell C-type lectin (LSECtin), and Galectin-3 have been proposed as alternative binding partners that play important roles in LAG3 function. Here, we used a fluorescent human T cell reporter system to study the function of LAG3. We found that LAG3 reduced the response to T cell receptor stimulation in the presence of MHC class II molecules to a lesser extent compared with the receptor programmed cell death protein 1. Analysis of deletion mutants demonstrated that the RRFSALE motif in the cytoplasmic tail of LAG3 was necessary and sufficient for LAG3-mediated inhibition. In this system, FGL1, but not LSECtin or Galectin-3, acted as a LAG3 ligand that weakly induced inhibition. LAG3-blocking antibodies attenuated LAG3-mediated inhibition in our reporter cells and enhanced reporter cell activation even in the absence of LAG3 ligands, indicating that they could potentially enhance T cell responses independently of their blocking effect.