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

• 批准号: 10666680
• 负责人: Laura A Solt
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/10666680
• 关键词: ATP-Binding Cassette Transporters; Acute; Aerobic; Affect; Anabolism; Autoimmunity; Binding; Cell Proliferation; Cell Survival; Cell membrane; Cell physiology; Cells; Cellular biology; Clonal Expansion; Compensation; Complex; Data; Dedications; 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 Induction; Hemopexin; Hepatocyte; Homeostasis; Immune; Immune response; Impairment; In Vitro; Individual; Infection; Injury; Iron; 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; 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

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.

摘要 有效的免疫反应包括将抗原特异性T细胞克隆扩增为效应细胞， 这是适应性免疫的基础。对这一过程至关重要的是，控制细胞新陈代谢、营养吸收 在能源需求高的电池中，支出是最重要的。血红素是一种含铁的金属有机化合物。 辅因子，是所有有氧生活的必需品。血红素既可以通过饮食获得，也可以在体内直接合成 细胞。它是一种中枢代谢和信号分子，调节多种生理活性物质。 从氧气利用到新陈代谢的各种过程。虽然过量时有潜在的毒性，但两者都缺乏 而过量的血红素会导致疾病。因此，微调的机制已经到位，以保持血红素 动态平衡。然而，由分子本身介导的血红素的重要性还没有得到很好的研究。 关于血红素是否对病理生理学有贡献，人们知之甚少。关于血红素调控的研究最多 已在红细胞和肝细胞中进行；对其他细胞中的血红素代谢知之甚少 类型，包括免疫细胞。而在健康个体的血浆中不能检测到血红素，在血管内 损伤、感染或自身免疫，急性期血红素清除蛋白水平升高， 被认为可以防止氧化损伤。血红素-血凝素复合体已被证明可以取代铁作为一种 T细胞的生长源，使T细胞能够增殖以竞争血红素铁源，这是一些病原体 用来成长。在多发性硬化症(MS)的小鼠模型EAE期间，血液连接蛋白水平升高，并 多发性硬化症患者升高。这些数据表明，血红素水平升高可能参与了疾病的发病机制。 关于血红素信号和代谢的一些最突出的问题涉及到要求 对于细胞功能的血红素进口与血红素生物合成。血红素输入的机制，包括一个 血红素转运体和细胞功能在很大程度上仍不清楚。我们的初步数据显示，血红素在 在T细胞的存活和增殖中起重要作用。胞外血红素耗竭对细胞有深远的影响 活性和增殖，而补充血红素可以挽救这些影响。我们还表明，细胞外 血红素的吸收以细胞器特有的方式补偿内源游离血红素的损失。总的来说，我们的 数据表明，细胞外的血红素对细胞的增殖和活性很重要，而细胞内的 衍生的血红素在信号的调节中起作用。根据我们的初步数据，我们假设 细胞血红素输入和生物合成之间的关系调节T效应细胞的增殖、存活和功能。我们 我将通过两个目的来验证我们的假设：(1)机械地探索外源血红素是否调节T辅助细胞 细胞存活和增殖；(2)确定辅助性T细胞功能对细胞内血红素的需求。 这些研究的完成将促进对血红素在T细胞生物学中的基本理解 细胞分子运输机制的鉴定、血红素的利用和分配。这些数据将 为血红素介导的病理和潜在的治疗选择提供关键信息。