通过 LAG-3 介导的 MHC II 类反式内吞作用间接抑制 CD4 T 细胞活化。
Indirect suppression of CD4 T cell activation through LAG-3-mediated trans-endocytosis of MHC class II.
发表日期：2024 Aug 21
作者：
Ei Wakamatsu, Hiroaki Machiyama, Hiroko Toyota, Arata Takeuchi, Ryuji Hashimoto, Haruo Kozono, Tadashi Yokosuka
来源：
Cell Reports
摘要：
免疫检查点受体的阻断在肿瘤免疫治疗中显示出出色的疗效。抗淋巴细胞激活基因 3 (LAG-3) 的治疗已被认为是下一个有效的治疗方法，但人们对 LAG-3 介导的免疫抑制机制的了解仍然有限。在这里，利用高分辨率分子成像，我们发现了通过 LAG-3 抑制 CD4 T 细胞的机制，其中抗原呈递细胞 (APC) 上的 LAG-3 结合的主要组织相容性复合体 (MHC) II 类分子聚集在免疫突触的中心区域，并通过 T 细胞受体驱动的内化运动转入表达 LAG-3 的 CD4 和 CD8 T 细胞。 APC 上 MHC II 类分子的下调会导致其抗原呈递功能减弱并损害 CD4 T 细胞活化。从这些数据来看，抗 LAG-3 治疗可有效直接阻断 LAG-3 的抑制信号传导，同时通过 LAG-3 介导的反式内吞作用减少 APC 上的 MHC II 类表达，从而从 T 细胞耗竭中恢复。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
Blockade of immune checkpoint receptors has shown outstanding efficacy for tumor immunotherapy. Promising treatment with anti-lymphocyte-activation gene-3 (LAG-3) has already been recognized as the next efficacious treatment, but there is still limited understanding of the mechanism of LAG-3-mediated immune suppression. Here, utilizing high-resolution molecular imaging, we find a mechanism of CD4 T cell suppression via LAG-3, in which LAG-3-bound major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) gather at the central region of an immunological synapse and are trans-endocytosed by T cell receptor-driven internalization motility toward CD4 and CD8 T cells expressing LAG-3. Downregulation of MHC class II molecules on APCs thus results in the attenuation of their antigen-presentation function and impairment of CD4 T cell activation. From these data, anti-LAG-3 treatment is suggested to have potency to directly block the inhibitory signaling via LAG-3 and simultaneously reduce MHC class II expression on APCs by LAG-3-mediated trans-endocytosis for recovery from T cell exhaustion.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.