Mechanisms by which selenium influences T helper cells during immune responses

描述（由申请人提供）：硒（Se）补充剂的免疫增强作用使其成为一种有前途的补充和替代医学（CAM）模式，用于增强对普通感冒，流感和疫苗接种的免疫力。硒补充剂还可以提供一种廉价而有效的手段，逆转与衰老相关的免疫力下降以及与癌症、癌症治疗和艾滋病毒/艾滋病相关的免疫抑制。然而，并不是所有类型的免疫应答都能通过补充硒得到同等程度的增强。其原因尚不清楚，因为对这种必需微量营养素影响免疫系统的机制了解不足。特别是，关于硒对树突状细胞（DC）和CD 4 + T细胞的影响的信息有限，尽管这些细胞在启动和形成免疫反应中起着至关重要的作用。本项目的目的是确定硒如何通过特定的硒蛋白的作用，影响不同类型的免疫应答过程中CD 4 + T细胞的活化，增殖和分化。我们计划测试以下具体目标： 具体目标1。确定增加膳食硒水平对CD 4 + T细胞活化、分化和增殖的影响。 具体目标2。鉴定调节CD 4 + T细胞活化的特定硒蛋白。 我们的实验设计涉及喂养低（0.08 ppm），中（0.25 ppm），或高（1.0 ppm）硒含量的小鼠饮食。所用的硒浓度反映了人类饮食中硒含量处于中等偏低、适当或补充水平。对于特定目的1，这些小鼠将用于评估Se状态对活化的CD 4 + T细胞的表型和功能的影响。研究设计将包括使用纯化的CD 4 + T细胞（用平板结合的抗CD 3/CD 28刺激）进行的实验、使用原代DC和SMARTA TCR转基因CD 4 + T细胞进行的抗原呈递试验，以及使用Th 1或Th 2型抗原激发进行的体内免疫。将使用已建立的技术分析CD 4 + T细胞的增殖和分化。对于特定目标2，实验将集中于定位于ER的硒蛋白，以确定每个在Ca++动员和T细胞活化中的潜在作用。每种常驻ER硒蛋白的水平将通过siRNA降低，并且将进行对CD 4 + T细胞活化的影响，并且确定Ca++依赖性细胞信号传导事件的影响。这一新发现的知识将对指导使用硒补充剂作为优化免疫反应的CAM模式产生重大影响。 公共卫生相关性：硒补充剂的免疫增强作用使其成为一种有前途的补充和替代医学（CAM）模式，以提高免疫力。然而，硒影响免疫应答的类型以及硒影响免疫应答的机制尚不清楚。该项目的目标是确定这种有效的抗氧化剂影响免疫系统的机制，旨在为硒补充剂的最佳使用提供重要的一步。

DESCRIPTION (provided by applicant): The immune-enhancing effects of selenium (Se) supplementation make it a promising complementary and alternative medicine (CAM) modality for boosting immunity against common colds, influenza, and vaccinations. Se supplementation may also provide an inexpensive and effective means of reversing the declining immunity associated with aging and the immunosuppression associated with cancer, its treatment, and with HIV/AIDS. However, not all types of immune responses are equivalently enhanced by Se supplementation. The reasons for this are unclear due to an inadequate understanding of the mechanisms by which this essential micronutrient affects the immune system. In particular, limited information is available regarding the effects of Se on dendritic cells (DCs) and CD4+ T cells, despite the crucial role that these cells play in initiating and shaping immune responses. The objective of this project is to determine how Se, through the actions of specific selenoproteins, influences the activation, proliferation, and differentiation of CD4+ T cells during different types of immune responses. We plan to test the following specific aims: Specific Aim 1. Determine the effect of increasing levels of dietary Se on the activation, differentiation, and proliferation of CD4+ T cells. Specific Aim 2. Identify specific selenoproteins that regulate the activation of CD4+ T cells. Our experimental design involves feeding mice diets that are low (0.08 ppm), medium (0.25 ppm), or high (1.0 ppm) in Se content. The Se concentrations to be used reflect human diets with Se content at moderately low, adequate, or supplemented levels. For Specific Aim 1, these mice will be used to assess the affects of Se status on the phenotype and function of activated CD4+ T cells. The study design will include experiments using purified CD4+ T cells stimulated with plate-bound anti-CD3/CD28, antigen presentation assays using primary DCs and SMARTA TCR-transgenic CD4+ T cells, and in vivo immunizations with either Th1- or Th2-type antigen challenges. The proliferation and differentiation of the CD4+ T cells will be analyzed using established techniques. For Specific Aim 2, experiments will focus on selenoproteins localized to the ER to determine potential roles of each in Ca++ mobilization and T cell activation. Levels of each resident ER selenoprotein will be reduced by siRNA and the effects on activation of CD4+ T cells will be carried out and the effects of Ca++-dependent cell signaling events determined. This newfound knowledge will have a significant impact on guiding the use of Se-supplementation as a CAM modality for optimizing immune responses. Public Health Relevance: The immune enhancing effects of Se supplementation make it a promising complementary and alternative medicine (CAM) modality for boosting immunity. However, the types of immune responses influenced by Se as well as the mechanisms by which Se affects immune responses are not clear. The goal of this project is to determine the mechanisms by which this potent antioxidant affects the immune system with the intent of providing an important step toward optimal use of Se supplementation.