Identification of cellular heme transport receptors that regulate T cell function

调节 T 细胞功能的细胞血红素转运受体的鉴定

基本信息

批准号：
10539212
负责人：
Laura A Solt
金额：
$ 28.98万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539212
关键词：
ATP-Binding Cassette Transporters Acute Aerobic Affect Anabolism Autoimmunity Cell Proliferation Cell Survival Cell membrane Cell physiology Cells Cellular biology Clonal Expansion Complex Data Development Diet Disease Effector Cell Enzymes Erythrocytes Expenditure Experimental Autoimmune Encephalomyelitis Functional disorder Genetic Transcription Goals Growth Helper-Inducer T-Lymphocyte Heme Heme Iron Hemolysis Hemopexin Hepatocyte Homeostasis Immune Immune response Impairment In Vitro Individual Infection Injury Iron Lead Life Measures Mediating Metabolic Metabolism Metalloproteins Multiple Sclerosis Nutrient Organelles Oxygen Pathogenesis Pathology Phase Physiological Processes Plasma Play Process Proliferating Proteins RNA Interference Regulation Reporter Reporting Research Role Signal Transduction Signaling Molecule Source Specificity Supplementation T cell differentiation T-Lymphocyte Testing Transport Process Warburg Effect Work absorption adaptive immunity antigen-specific T cells base cell injury cell type cofactor effector T cell extracellular heme a heme biosynthesis iron deficiency knock-down mouse model multiple sclerosis patient oxidative damage pathogen prevent receptor response solute trafficking uptake

项目摘要

SUMMARY An effective immune response involves the clonal expansion of antigen specific T cells into effector cells, which is fundamental to adaptive immunity. Critical to this process, control of cellular metabolism, nutrient uptake and expenditure is paramount in cells with high-energy demand. Heme is an iron containing metallo-organic cofactor and essential for all aerobic life. Heme can either be acquired through diet or directly synthesized in cells. It acts as a central metabolic and signaling molecule regulating a diverse number of physiological processes ranging from oxygen utilization to metabolism. While potentially toxic when in excess, both deficiency and overload of heme can lead to disease. As a result, finely tuned mechanisms are in place to maintain heme homeostasis. However, the importance of heme, mediated by the molecule itself, has been marginally studied. Whether heme can contribute to pathophysiology is poorly understood. Most studies on heme regulation have been performed in erythrocytes and hepatocytes; very little is known about heme metabolism in other cell types, including immune cells. While heme is not detectable in plasma of healthy individuals, during intravascular injury, infection, or autoimmunity, levels of the acute phase heme scavenging protein, hemopexin, increase which is thought to prevent oxidative damage. Heme-hemopexin complexes have been shown to replace iron as a growth source in T cells, enabling T cells to proliferate to compete for heme-iron sources, which some pathogens use for growth. Hemopexin levels increase during EAE, a mouse model of multiple sclerosis (MS) and are increased in MS patients. These data suggest elevated heme levels may contribute to disease pathogenesis. Some of the top outstanding questions regarding heme signaling and metabolism involve the requirement for heme import versus heme biosynthesis for cellular function. The mechanisms of heme import, including a heme transporter, and cellular functions remain largely unknown. Our preliminary data demonstrate heme plays a significant role in T cell survival and proliferation. Extracellular heme depletion has a profound effect on cell viability and proliferation whereas heme supplementation rescues these effects. We also show that extracellular heme uptake compensates for loss of endogenous free heme in an organelle-specific manner. Collectively, our data suggest that extracellular heme is important for cellular proliferation and viability whereas intracellularly derived heme functions in regulation of signaling. Given our preliminary data we hypothesize that coordination between cellular heme import and biosynthesis regulates T effector cell proliferation, survival, and function. We will test our hypothesis through two Aims: (1) Mechanistically exploring if exogenous heme regulates T helper cell survival and proliferation; (2) Determining the requirement for intracellular heme in T helper cell function. Completion of these studies will advance a fundamental understanding for heme in T cell biology through the identification of cellular molecular transport mechanisms, heme utilization, and distribution. These data will provide key information for heme-mediated pathologies and potential treatment options.

概括有效的免疫反应涉及抗原特异性 T 细胞克隆扩增为效应细胞，这是适应性免疫的基础。细胞代谢和营养吸收的控制对此过程至关重要对于能量需求较高的细胞来说，支出至关重要。血红素是一种含铁的金属有机物辅助因子，对所有有氧生命至关重要。血红素可以通过饮食获得，也可以直接合成细胞。它作为调节多种生理功能的中心代谢和信号分子从氧气利用到新陈代谢的过程。虽然过量时可能有毒，但两者缺乏时血红素过多会导致疾病。因此，微调机制就位以维持血红素体内平衡。然而，血红素的重要性（由分子本身介导）的研究很少。血红素是否有助于病理生理学尚不清楚。大多数关于血红素调节的研究已在红细胞和肝细胞中进行；关于其他细胞中的血红素代谢知之甚少类型，包括免疫细胞。虽然在健康个体的血浆中检测不到血红素，但在血管内损伤、感染或自身免疫，急性期血红素清除蛋白、血红素结合蛋白的水平会增加被认为可以防止氧化损伤。血红素-血红素复合物已被证明可以替代铁作为 T 细胞中的生长源，使 T 细胞能够增殖以竞争血红素铁源，某些病原体用于增长。血红素结合蛋白水平在 EAE（多发性硬化症 (MS) 小鼠模型）期间增加，并且 MS 患者中增加。这些数据表明血红素水平升高可能有助于疾病发病机制。关于血红素信号传导和代谢的一些最突出的问题涉及以下要求血红素输入与细胞功能的血红素生物合成。血红素输入机制，包括血红素转运蛋白和细胞功能仍然很大程度上未知。我们的初步数据证明了血红素的作用在 T 细胞存活和增殖中发挥重要作用。细胞外血红素耗竭对细胞产生深远影响活力和增殖，而血红素补充剂可以挽救这些影响。我们还表明，细胞外血红素摄取以细胞器特异性方式补偿内源性游离血红素的损失。总的来说，我们的数据表明，细胞外血红素对于细胞增殖和活力很重要，而细胞内血红素衍生血红素在信号传导调节中发挥作用。根据我们的初步数据，我们假设协调细胞血红素输入和生物合成之间调节效应 T 细胞的增殖、存活和功能。我们将通过两个目标来检验我们的假设：（1）从机制上探讨外源血红素是否调节 T 辅助细胞细胞存活和增殖； (2)确定T辅助细胞功能对细胞内血红素的需求。这些研究的完成将通过以下方式促进对 T 细胞生物学中血红素的基本了解识别细胞分子运输机制、血红素利用和分布。这些数据将提供血红素介导的病理学和潜在治疗方案的关键信息。