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LAG-3与稳定态-MHCII的结合限制了T细胞功能,抑制自身免疫和抗癌免疫
作者:小柯机器人 发布时间:2022/4/16 19:29:04

日本东京大学定量生物科学研究所Taku Okazaki团队近期取得重要共作进展,他们研究发现LAG-3与稳定态-MHCII的结合限制了T细胞功能,抑制自身免疫和抗癌免疫。该项研究成果2022年4月11日在线发表于《免疫学》杂志上。

在这里,小组成员探究了潜在配体、稳定肽-MHC II 类复合物 (pMHCII) 和纤维蛋白原样蛋白1 (FGL1) 对 LAG-3 体外和体内活性的相对贡献。 LAG-3与稳定的pMHCII结合但不与 FGL1 结合可在体外诱导T细胞抑制。一致地,缺乏FGL1结合能力的LAG-3突变体,而不是那些缺乏稳定pMHCII结合能力的突变体,在体外保留了抑制活性。因此,在NOD小鼠中,LAG-3的稳定pMHCII结合能力而非FGL1结合能力的靶向破坏,重现了LAG-3缺乏导致的糖尿病恶化。此外,与C57BL/6小鼠中LAG-3缺乏相比,LAG-3与pMHCII稳定结合能力的丧失增强了抗癌免疫力。

这些结果将稳定的pMHCII鉴定为LAG-3在自身免疫和抗癌免疫中的功能性配体。因此,稳定的pMHCII-LAG-3 相互作用是人类疾病的潜在治疗靶标。

据介绍,淋巴细胞活化基因3 (LAG-3) 是一种有效的抑制性辅助受体;然而,它的功能性配体仍然不清楚,目前已经确定出了不同的潜在配体。

附:英文原文

Title: Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity

Author: Takumi Maruhashi, Daisuke Sugiura, Il-mi Okazaki, Kenji Shimizu, Takeo K. Maeda, Jun Ikubo, Harunori Yoshikawa, Katsumi Maenaka, Naozumi Ishimaru, Hidetaka Kosako, Tatsuya Takemoto, Taku Okazaki

Issue&Volume: 2022-04-11

Abstract: Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, itsfunctional ligand remains elusive, with distinct potential ligands identified. Here,we investigated the relative contribution of potential ligands, stable peptide-MHCclass II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activityin 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 lackingstable pMHCII-binding capacity retained suppressive activity in vitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacityof 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 immunitycomparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCIIas 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.

DOI: 10.1016/j.immuni.2022.03.013

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00136-4

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx