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

硒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，包括最佳的免疫反应。硒的生物学效应主要是通过其作为氨基酸--硒半胱氨酸(Sec)掺入硒蛋白中来实现的。已在人类中鉴定出25种硒蛋白，除了一种外，所有这些蛋白在小鼠和大鼠中也以含有SEC的蛋白的形式存在。我们已经发现的一种对最佳免疫反应重要的硒蛋白是内质网(ER)酶硒蛋白I(SELENOI)。在刺激的T细胞中，SELENOI的表达增加，并且对Se摄入量的水平很敏感。我们研究产品的主要目标是充分了解SELENOI在调节T细胞反应中所起的作用。我们的中心假设是，SELENOI在肯尼迪合成途径中起到合成磷脂酰乙醇胺(PE)的作用，在T细胞激活过程中，对PE的需求增加，这需要在SELENOI合成的从头合成中加入更高水平的Se。这反过来会导致更高水平的PE并入细胞膜。在低硒或遗传缺陷的条件下，SELENOI的表达和活性降低，膜刚性和其他膜特性受损，导致T细胞信号、增殖和分化受损。我们的创新研究将最终确定SELENOI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。我们将实现以下特定目标：特定目标1.确定SELENOI在T细胞PE合成中的作用及其对建立平衡的膜脂组成和促进强大的TCR诱导信号的要求。具体目的2.阐明SELENOI促进T细胞有效增殖和分化的机制。具体目的3.确定SELENOI在T细胞对疫苗和病毒病原体的反应中的体内作用。

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.