The role of selenoprotein I in phospholipidethanolamine dependent mechanisms that regulate T cell activation

硒（Se）是一种必需的微量营养素，对人类健康的许多方面都很重要，包括最佳免疫反应。硒的生物学效应主要是通过其作为氨基酸硒代半胱氨酸（Sec）掺入硒蛋白而发挥的。在人类中已经鉴定出25种硒蛋白，其中除了一种之外，所有的硒蛋白也以含Sec蛋白的形式存在于小鼠和大鼠中。我们发现对最佳免疫应答很重要的一种硒蛋白是内质网（ER）酶硒蛋白I（SELENOI）。在受刺激的T细胞中，硒的表达增加，并且对硒摄入水平敏感。我们研究产品的主要目标是充分了解SELENOI在调节T细胞反应中发挥的作用。我们的中心假设是，硒在肯尼迪合成途径中起合成磷脂酰乙醇胺（PE）的作用，并且在T细胞活化期间，对PE的需求增加，这需要更高水平的Se掺入从头合成的硒中。这反过来又导致更高水平的PE掺入细胞膜。在低Se或降低SELENOI表达和活性的遗传缺陷的条件下，膜刚性以及导致受损的T细胞信号传导、增殖和分化的其他膜性质受损。我们的创新研究将明确确定硒在PE生物合成中的作用，以及这如何影响T细胞功能和免疫反应。我们将实现以下具体目标：具体目标1.确定硒在T细胞PE合成中的作用及其建立平衡的膜脂质组成和促进稳健的TCR诱导信号的需求。具体目标2。阐明SELENOI促进有效T细胞增殖和分化的机制。具体目标3。确定SELENOI在T细胞对疫苗和病毒病原体应答中的体内作用。

Selenium (Se) is an essential micronutrient important for many aspects of human health, including optimal immune responses. The biological effects of Se are exerted mainly through its incorporation into selenoproteins as the amino acid, selenocysteine (Sec). Twenty-five selenoproteins have been identified in humans, all but one of which also exist as Sec-containing proteins in mice and rats. One selenoprotein that we have found to be important for optimal immune responses is the endoplasmic reticulum (ER) enzyme selenoprotein I (SELENOI). SELENOI expression is increased in stimulated T cells and is sensitive to levels of Se intake. The main goal of our research product is to fully understand the role that SELENOI plays in regulating T cell responses. Our central hypothesis is that SELENOI functions to synthesize phosphatidylethanolamine (PE) in the Kennedy synthesis pathway, and during activation of T cells there is increased demand for PE that requires higher levels of Se incorporated into SELENOI synthesized de novo. This in turn leads to higher levels of PE incorporated into cellular membranes. In conditions of low Se or genetic defects that reduce SELENOI expression and activity, membrane rigidity is compromised as well as other membrane properties that lead to impaired T cell signaling, proliferation, and differentiation. Our innovative studies will definitively determine the role of SELENOI in PE biosynthesis and how this affects T cell function and immune responses. We will accomplishment of the following specific aims: Specific Aim 1. To determine the role of SELENOI in PE synthesis in T cells and its requirement for establishing balanced membrane lipid composition and promoting robust TCR induced signals. Specific Aim 2. To elucidate mechanisms by which SELENOI promotes effective T cell proliferation and differentiation. Specific Aim 3. To determine the in vivo role of SELENOI in T cell responses to vaccines and a viral pathogen.