LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.

Cancers and chronic infectious pathogens often evade immune-mediated elimination by suppressing T cell function via engaging inhibitory receptors expressed on T cells. The phospholipid lysophosphatidic acid (LPA) is often increased systemically from basal concentrations upon development of cancer and chronic infections. We previously showed that, at these elevated concentrations, LPA suppresses the ability of CD8 T cells to kill malignant cells and to control tumor growth. Here, we demonstrate that LPA signaling suppresses T cell function via disrupting T cell receptor–induced cytoskeletal dynamics, immune synapse formation, signal transduction, and the tubulin code. This report identifies a targetable mechanism of receptor-mediated inhibition of T cell function that could be used in combination therapies to enhance antitumor and antiviral immunity. Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-specific T cell:target cell formation, IP3R1 localizes to the IS by a process dependent on mDia1 and actin and microtubule polymerization. LPA not only inhibited IP3R1 from reaching the IS but also altered T cell receptor (TCR)–induced localization of RhoA and mDia1 impairing F-actin accumulation and altering the tubulin code. Consequently, LPA impeded calcium store release and IS-directed cytokine secretion. Thus, targeting LPA signaling in chronic inflammatory conditions may rescue T cell function and promote antiviral and antitumor immunity.

癌症和慢性感染病原体常常通过与T细胞上表达的抑制性受体结合来抑制T细胞功能，从而逃避免疫介导的清除。磷脂溶血磷脂酸（LPA）在癌症和慢性感染发生时，其全身浓度通常会从基础水平升高。我们之前表明，在这些升高的浓度下，LPA会抑制CD8 T细胞杀伤恶性细胞和控制肿瘤生长的能力。在此，我们证明LPA信号通过破坏T细胞受体诱导的细胞骨架动力学、免疫突触形成、信号转导以及微管蛋白编码来抑制T细胞功能。本报告确定了一种可靶向的受体介导的T细胞功能抑制机制，可用于联合疗法以增强抗肿瘤和抗病毒免疫。 癌症和慢性感染常常会使生物活性脂质溶血磷脂酸（LPA）水平升高，我们已经证明，LPA在与CD8 T细胞上的LPAR5结合时作为一种抑制性配体，抑制细胞毒活性和肿瘤控制。这项使用人和小鼠原代T淋巴细胞的研究揭示了LPA如何通过竞争细胞骨架调节来破坏抗原特异性CD8 T细胞与靶细胞的免疫突触（IS）形成和T细胞功能。具体而言，我们发现，在抗原特异性T细胞与靶细胞形成时，IP3R1通过一个依赖于mDia1以及肌动蛋白和微管聚合的过程定位到免疫突触。LPA不仅抑制IP3R1到达免疫突触，还改变了T细胞受体（TCR）诱导的RhoA和mDia1的定位，损害F - 肌动蛋白的积累并改变微管蛋白编码。因此，LPA阻碍了钙库释放和免疫突触导向的细胞因子分泌。因此，在慢性炎症条件下靶向LPA信号可能恢复T细胞功能并促进抗病毒和抗肿瘤免疫。