Abstract：
Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, its functional ligand remains elusive, with distinct potential ligands identified. Here, we investigated the relative contribution of potential ligands, stable peptide-MHC class II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activity in vitro and in vivo. Binding of LAG-3 to stable pMHCII but not to FGL1 induced T cell suppression in vitro. Consistently, LAG-3 mutants lacking FGL1-binding capacity but not those lacking stable pMHCII-binding capacity retained suppressive activity in vitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacity of LAG-3 in NOD mice recapitulated diabetes exacerbation by LAG-3 deficiency. Additionally, the loss of stable pMHCII-binding capacity of LAG-3 augmented anti-cancer immunity comparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCII as a functional ligand of LAG-3 both in autoimmunity and anti-cancer immunity. Thus, stable pMHCII-LAG-3 interaction is a potential therapeutic target in human diseases.
摘要：
淋巴细胞活化基因-3(LAG-3)是一种有效的抑制性共受体,它的功能配体仍然难以捉摸，具有不同的潜在配体。这里,我们研究了潜在配体的相对贡献，稳定的肽-MHCII类复合物（pMHCII）和纤维蛋白原样蛋白1（FGL1），体外和体内的LAG-3活性。LAG-3与稳定的pMHCII而不是FGL1的结合在体外诱导了T细胞抑制。始终如一，缺乏FGL1结合能力的LAG-3突变体但缺乏稳定的pMHCII结合能力的LAG-3突变体在体外保留了抑制活性。因此，NOD小鼠中稳定的LAG-3pMHCII-而非FGL1-结合能力的靶向破坏,概括了LAG-3缺乏导致糖尿病恶化.此外,在C57BL/6小鼠中,与LAG-3缺乏相比,LAG-3的稳定pMHCII结合能力的丧失增强了抗癌免疫力.这些结果鉴定了稳定的pMHCII在自身免疫和抗癌免疫中均为LAG-3的功能配体。因此，稳定的pMHCII-LAG-3相互作用是人类疾病的潜在治疗靶点。
