Identification of cellular heme transport receptors that regulate T cell function

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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.