VISTA蛋白是PSGL-1受体的酸性pH选择性配体
作者：小柯机器人 发布时间：2019/10/24 16:38:45
美国百时美施贵宝公司Robert J. Johnston等研究人员发现，VISTA蛋白是PSGL-1受体的酸性pH选择性配体。相关论文发表在2019年10月24日出版的《自然》杂志。
研究人员发现，T细胞活化的V结构域免疫球蛋白抑制蛋白（VISTA）在酸性pH下（例如在肿瘤微环境中）选择性地参与和抑制T细胞。沿VISTA细胞外结构域边缘的多个组氨酸残基介导粘附和共抑制受体P-选择蛋白糖蛋白配体1（PSGL-1）的结合。经过改造以在酸性环境中选择性结合并阻断这种相互作用的抗体，足以逆转VISTA介导的体内免疫抑制作用。这些发现确定了VISTA可能引起对抗肿瘤免疫反应的抗性机制，以及pH在免疫共受体参与中的出乎意料的决定性作用。
据介绍，共抑制性免疫受体可导致癌症患者的T细胞功能障碍。针对细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性细胞死亡1蛋白（PD-1）的封闭抗体部分逆转了这种作用，并且在越来越多的恶性肿瘤中成为治疗标准。然而，人们尚未完全理解使肿瘤变得不适用于T细胞的许多其他信号轴。
附：英文原文
Title:VISTA is an acidic pH-selective ligand for PSGL-1
Author:Robert J. Johnston, Linhui Julie Su, […]Alan J. Korman
Issue&Volume:Volume 574 Issue 7779
Abstract: Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.
DOI:10.1038/s41586-019-1674-5
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：43.07
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html