Identification of cellular heme transport receptors that regulate T cell function

总结 有效的免疫应答包括抗原特异性T细胞克隆扩增成效应细胞， 这是适应性免疫的基础。对这个过程至关重要的是，控制细胞代谢，营养吸收 并且消耗在具有高能量需求的电池中是最重要的。血红素是一种含铁的金属有机物 是所有有氧生活的辅助因子和必需品。血红素既可以通过饮食获得，也可以直接在体内合成。 细胞它作为一个中心的代谢和信号分子调节多种生理 从氧利用到新陈代谢的过程。虽然过量时可能有毒，但缺乏 血红素过量会导致疾病因此，精细调整的机制到位，以维持血红素 体内平衡然而，血红素的重要性，介导的分子本身，已被边缘研究。 血红素是否可以有助于病理生理学知之甚少。关于血红素调节的研究 在红细胞和肝细胞中进行了研究，但对血红素在其他细胞中的代谢知之甚少 包括免疫细胞。虽然血红素在健康个体的血浆中不可检测，但在血管内给药期间， 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增加， 可以防止氧化损伤。血红素-血红素结合蛋白复合物已被证明可取代铁， T细胞中的生长源，使T细胞能够增殖以竞争血红素铁源，这是一些病原体 用于增长。在EAE（多发性硬化症（MS）的小鼠模型）期间，血液结合蛋白水平增加， 在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的发病机制。 关于血红素信号传导和代谢的一些最突出的问题涉及到 血红素输入与血红素生物合成的细胞功能。血红素输入的机制，包括 血红素转运蛋白和细胞功能仍然是未知的。我们的初步数据表明血红素 在T细胞存活和增殖中起重要作用。细胞外血红素耗竭对细胞的生长和分化有着深远的影响。 存活力和增殖，而血红素补充挽救了这些作用。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。总体而言，我们 数据表明，细胞外血红素对细胞增殖和活力是重要的， 衍生的血红素在信号传导调节中起作用。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的相互作用调节T效应细胞增殖、存活和功能。我们 本文将从两个方面来验证我们的假设：（1）探讨外源性血红素对T辅助细胞的调节机制 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对血红素在T细胞生物学中的作用的研究， 细胞分子转运机制、血红素利用和分布的鉴定。这些数据将 为血红素介导的病理学和潜在的治疗方案提供关键信息。

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.