溶血磷脂酸（LPA）是一种内源性生物活性脂质，通过同源性LPA受体，即Gs蛋白耦合受体（GPCRs），外泌体产生并信号传递到细胞。在小鼠和人体内，成熟淋巴细胞表达三种LPA受体，即LPA2、LPA5和LPA6，我们的研究表明，T淋巴细胞通过LPA5信号抑制特异性抗原受体信号通路，最终影响淋巴细胞的活化、增殖和功能。本文回顾和讨论了以LPA-LPA5轴作为外周免疫耐受机制抑制适应性免疫的先前与正在进行的研究工作，但在慢性炎症情况下被转化。具体而言，发现LPA-LPA5信号在至少两个机制上通过调节肿瘤免疫过程中的效应细胞CD8T细胞：（i）调节肿瘤效应细胞和特异性抗原靶细胞之间的免疫突触形成，从而直接影响细胞毒性活性；（ii）改变T细胞代谢，使其依赖脂肪酸氧化和减少代谢效率进行线粒体呼吸。LPA5抑制活性的体内结果影响CD8T细胞杀伤和肿瘤免疫，并促使考虑采用LPA5拮抗剂治疗恶性肿瘤和慢性感染。©2023 John Wiley & Sons A/S。由John Wiley ＆Sons Ltd.发布

Lysophosphatidic acid (LPA) is an endogenous bioactive lipid that is produced extracellularly and signals to cells via cognate LPA receptors, which are G-protein coupled receptors (GPCRs). Mature lymphocytes in mice and humans express three LPA receptors, LPA2 , LPA5, and LPA6 , and work from our group has determined that LPA5 signaling by T lymphocytes inhibits specific antigen-receptor signaling pathways that ultimately impair lymphocyte activation, proliferation, and function. In this review, we discuss previous and ongoing work characterizing the ability of an LPA-LPA5 axis to serve as a peripheral immunological tolerance mechanism that restrains adaptive immunity but is subverted during settings of chronic inflammation. Specifically, LPA-LPA5 signaling is found to regulate effector cytotoxic CD8 T cells by (at least) two mechanisms: (i) regulating the actin-microtubule cytoskeleton in a manner that impairs immunological synapse formation between an effector CD8 T cell and antigen-specific target cell, thus directly impairing cytotoxic activity, and (ii) shifting T-cell metabolism to depend on fatty-acid oxidation for mitochondrial respiration and reducing metabolic efficiency. The in vivo outcome of LPA5 inhibitory activity impairs CD8 T-cell killing and tumor immunity in mouse models providing impetus to consider LPA5 antagonism for the treatment of malignancies and chronic infections.© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.