The role of SPNS2 in T cell responses

SPNS2 在 T 细胞反应中的作用

• 批准号: 10058236
• 负责人: Susan Ruth Schwab
• 金额: $ 43.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058236
• 关键词: Address; Affect; Autoimmune Responses; Autoimmunity; Back; Blood; Blood Circulation; Blood Vessels; Bradycardia; CD8-Positive T-Lymphocytes; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Cell Survival; Cell physiology; Cells; Colitis; Data; Disease; Drug Targeting; Drug usage; Endothelial Cells; Exhibits; FDA approved; G-Protein-Coupled Receptors; Generations; Grant; Helper-Inducer T-Lymphocyte; Homeostasis; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Inorganic Phosphate Transporter; Lipids; Lung; Lymph; Lymphatic Endothelial Cells; Lymphocyte; Memory; Mitochondria; Multiple Sclerosis; Mus; Neuraxis; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Psoriasis; Role; Signal Transduction; Site; Sphingosine-1-Phosphate Receptor; Spleen; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Travel; Vascular Permeabilities; insight; lymph nodes; lymphoid organ; macular edema; new therapeutic target; novel; phase II trial; prevent; residence; secondary lymphoid organ; side effect; sphingosine 1-phosphate; targeted treatment

Project Summary The signaling lipid sphingosine 1-phosphate (S1P) plays many roles in the immune response. Most notably, S1P regulates lymphocyte exit from lymphoid organs, where they are initially activated, into circulation, where they can travel to the site of infection. The concentration of S1P is higher in lymph than lymph nodes (LN). This gradient guides lymphocytes out of the LN into lymph and ultimately back to blood. Similarly, the high S1P within blood attracts lymphocytes to exit the spleen into circulation. T cells sense the S1P gradient primarily through the G protein-coupled receptor S1P receptor 1 (S1PR1). FTY720, a drug that targets four S1P receptors including S1PR1, became the first FDA-approved oral therapeutic for multiple sclerosis. By blocking lymphocyte exit from lymphoid organs, FTY720 prevents lymphocytes from accessing the central nervous system. Second-generation drugs that target S1PR1 have also shown promise in Phase II trials for psoriasis and colitis. Unfortunately, use of these drugs is limited because they also target S1PR1 in endothelial cells and cardiomyocytes, resulting in serious side effects. We recently found that the major facilitator superfamily transporter SPNS2 supplies S1P into lymph but not blood, making it a promising new drug target that would enable spatially specific modulation of S1P signaling. Blood S1P levels remain at about 80% of baseline in SPNS2-deficient mice, and these mice exhibit normal lung vascular permeability, unlike FTY720-treated mice. By contrast, S1P levels in lymph are dramatically reduced in SPNS2-deficient mice. In SPNS2-deficient mice, T cells exit the spleen into blood normally but cannot exit LN into lymph, leading to a redistribution of T cells from spleen to LN and a loss of circulating cells. We proposed that targeting SPNS2 could trap T cells in LN without substantial cardiovascular side effects. However, these studies were carried out in homeostasis, and the role of SPNS2 during inflammation or disease is poorly understood. Here, we will investigate how SPNS2 affects T cell function during the effector and memory stages of an immune response. First, we will address whether SPNS2 generates the lymph S1P that guides T cell exit from LN during an immune response, or whether in inflammation other transporters are upregulated and can compensate for SPNS2's loss. This is the key question to determine whether SPNS2 would be an effective drug target. Second, we will test the hypothesis that SPNS2 supplies S1P into the LN parenchyma during an inflammatory response, blunting the gradient that guides exit and slowing (but not halting) T cell transit through an inflamed LN. Third, we will determine whether SPNS2 regulates memory T cell differentiation and survival, extending our surprising finding that SPNS2/S1PR1 signaling regulates mitochondrial content and survival in naïve T cells. The proposed aims will test SPNS2's potential as a target for immunosuppressive therapy, and advance our basic understanding of the role of S1P in the immune response.

项目摘要 信号脂质鞘氨醇1-磷酸（S1 P）在免疫应答中起着许多作用。最 值得注意的是，S1 P调节淋巴细胞从淋巴器官（它们在淋巴器官中被初始激活）进入循环， 在那里它们可以到达感染的地方。淋巴液中S1 P浓度高于淋巴结 （LN）。这种梯度引导淋巴细胞从LN进入淋巴并最终返回血液。类似地， 血液中的高S1 P吸引淋巴细胞离开脾脏进入循环。T细胞感知S1 P梯度 主要通过G蛋白偶联受体S1 P受体1（S1 PR 1）。FTY 720，一种针对四种 包括S1 PR 1在内的S1 P受体成为第一个FDA批准的多发性硬化症口服治疗药物。通过 FTY 720阻断淋巴细胞从淋巴器官的出口，阻止淋巴细胞进入中枢神经系统。 神经系统针对S1 PR 1的第二代药物也在II期试验中显示出希望， 牛皮癣和结肠炎。不幸的是，这些药物的使用是有限的，因为它们也靶向S1 PR 1， 内皮细胞和心肌细胞，导致严重的副作用。我们最近发现， 易化超家族转运蛋白SPNS 2将S1 P供应到淋巴中，但不供应到血液中，使其成为一种有前途的新转运蛋白 药物靶点，这将使空间特异性调节S1 P信号传导。血液S1 P水平保持在约 在SPNS 2缺陷小鼠中为基线的80%，并且这些小鼠表现出正常的肺血管通透性，不像 FTY 720处理的小鼠。相比之下，SPNS 2缺陷小鼠淋巴中的S1 P水平显著降低。在 在SPNS 2缺陷小鼠中，T细胞正常地离开脾脏进入血液，但不能离开LN进入淋巴，导致T细胞在淋巴细胞中的比例降低。 T细胞从脾向LN的重新分布和循环细胞的损失。我们提出针对SPNS 2 可以捕获LN中的T细胞，而没有实质性的心血管副作用。然而，这些研究进行了 在体内平衡中，SPNS 2在炎症或疾病中的作用知之甚少。在这里，我们将 研究SPNS 2如何在免疫应答的效应和记忆阶段影响T细胞功能。 首先，我们将讨论SPNS 2是否产生淋巴S1 P，该淋巴S1 P在淋巴结转移过程中引导T细胞从LN中退出。 免疫应答，或者是否在炎症中其他转运蛋白被上调并可以补偿 SPNS 2的损失这是决定SPNS 2是否是有效药物靶点的关键问题。 第二，我们将检验SPNS 2在炎症过程中向LN实质提供S1 P的假设。 反应，钝化梯度，引导出口和减缓（但不停止）T细胞过境通过发炎 LN.第三，我们将确定SPNS 2是否调节记忆T细胞的分化和存活， 我们令人惊讶的发现，SPNS 2/S1 PR 1信号调节幼稚T细胞的线粒体含量和存活， 细胞这些目标将测试SPNS 2作为免疫抑制治疗靶点的潜力，并推动SPNS 2的研究。 我们对S1 P在免疫反应中的作用的基本理解。