Glucocorticoid/Stress Effects on Dendritic Cell Function

糖皮质激素/应激对树突状细胞功能的影响

• 批准号: 7341693
• 负责人: ROBERT H. BONNEAU
• 金额: $ 34.44万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341693
• 关键词: Address; Affect; Antigen Presentation; Antigen Presentation Pathway; Antigens; Antiviral Agents; Applications Grants; Area; Bacterial Infections; CD8B1 gene; Cell Maturation; Cell physiology; Cell surface; Cells; Class; Corticosterone; Cross Presentation; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Disease; Ensure; Event; Foundations; Generations; Glucocorticoids; Goals; Histocompatibility Antigens Class I; Immune; Immune response; Immunity; Impairment; In Vitro; Infection; Knowledge; Link; Lymphocyte; Lymphocyte Function; MHC Class I Genes; Mediating; Memory; Molecular; Mus; Neurosecretory Systems; Pathway interactions; Peptides; Phenotype; Play; Predisposition; Process; Production; Psychological Stress; Publishing; Qualifying; Range; Reagent; Refractory; Regulation; Research; Research Personnel; Role; Simplexvirus; Stress; Sympathetic Nervous System; T-Lymphocyte; Testing; Time; Transport Process; Vaccination; Viral; Virus; Virus Diseases; Work; antigen processing; cell type; cytotoxic; experience; hypothalamic-pituitary-adrenal axis; immune function; in vivo; innovation; pathogen; peptide hormone; programs; response; tumor; uptake; vaccination strategy

There is substantial evidence for psychological stress-induced, neuroendocrine-mediated modulation of mmune function. The long-range goal of this program is to define the cellular and molecular mechanisms by which psychological stress and its associated increase in corticosterone affect CD8+ cytotoxic T lymphocyte (CTL) responses. An efficient and robust CD8+ CTL lymphocyte response is necessary for the successful defense against many diseases that are immunologically resisted, in particular, virus infections and some tumors. The efficiency and robustness of this response is absolutely dependent upon the efficient functioning of dendritic cells. Dendritic cells must process and present sufficient antigen at the right time and in the right place for successful activation of CD8+ T cells. Any impairment of these critical functions will undermine CD8+ T cell responses. Thus, an understanding of stress/corticosterone-mediated suppression of CD8+ T cell immunity is incomplete without an understanding of the effects of stress/corticosterone on dendritic cells. Knowledge of the cellular and molecular processes involved in antigen processing and presentation and dendritic cell function provide a unique opportunity to dissect the mechanisms underlying stress-associated regulation of immune function. Therefore, our current objective is to use this knowledge to test the hypothesis that stress and stress-associated increases in corticosterone modulate dendritic cell function. Specifically, we address those functions associated with dendritic cell maturation, and the ability of dendritic cells to process and present MHC class l-restricted antigen and induce antigen-specific CTL. These studies specifically focus on both direct- and cross-presentation pathways of antigen presentation and on the activation and maturation of dendritic cells that are required to ensure a protective CTL response. To achieve this objective, three specific aims are proposed: (I) To determine the sub-cellular mechanism of action of corticosterone on the direct pathway of MHC class I antigen processing and presentation; (II) To determine the effect of glucocorticoids and stress on cross-presentation in vitro and in vivo and; (III) To determine the effect of glucocorticoids and stress on dendritic cell maturation and function in vitro and in vivo. The rationale for the proposed research is that an understanding of the impact of corticosterone and stress on dendritic cell antigen presentation and maturation is a critical link to understanding the mechanisms by which stress-induced glucocorticoids influence the development of naturally-derived immunity and immunity that is elicited by vaccination. At the completion of this project we will expect to have identified those components of crucial dendritic cell functions that are affected by stress and glucocorticoids and the resulting impact on the generation of CD8+ CTL responses.

有大量证据表明，心理应激诱导的、神经内分泌调节的 免疫功能。这个项目的长期目标是确定细胞和分子机制。 心理应激及其相关皮质酮增加对CD8+细胞毒T细胞的影响 淋巴细胞(CTL)反应。一个高效和强大的CD8+CTL淋巴细胞反应对于 成功地防御许多免疫抵抗的疾病，特别是病毒感染 还有一些肿瘤。这种响应的效率和健壮性完全取决于 树突状细胞的功能。树突状细胞必须在正确的时间处理和呈递足够的抗原 在正确的位置成功激活CD8+T细胞。这些关键功能的任何损害都将 破坏CD8+T细胞反应。因此，理解应激/皮质酮介导的抑制 如果不了解应激/皮质酮对CD8+T细胞免疫的影响，CD8+T细胞免疫是不完整的 树突状细胞。了解参与抗原处理的细胞和分子过程以及 呈递和树突状细胞功能提供了一个独特的机会来剖析潜在的机制 应激相关的免疫功能调节。因此，我们目前的目标是利用这一知识 为了验证应激和应激相关的皮质酮增加调制树突状细胞的假说 功能。具体地说，我们讨论了与树突状细胞成熟相关的那些功能，以及 树突状细胞处理并呈递MHC类L限制性抗原，诱导抗原特异性CTL。 这些研究特别侧重于抗原提呈的直接和交叉递呈途径以及 树突状细胞的激活和成熟是确保保护性CTL反应所必需的。至 为了实现这一目标，提出了三个具体的目标：(1)确定细胞的亚细胞机制 皮质酮在MHC-I类抗原处理和递呈的直接途径中的作用；(Ii) 确定糖皮质激素和应激对体外和体内交叉呈现的影响； 测定糖皮质激素和应激对树突状细胞成熟和功能的影响 活着。拟议研究的基本原理是，了解皮质酮和皮质酮的影响 树突状细胞抗原提呈和成熟的压力是理解 应激诱导的糖皮质激素影响自然衍生性痴呆发生的机制 免疫力和由接种疫苗引起的免疫力。在这个项目完成后，我们预计将 已经确定了那些关键的树突状细胞功能的成分，这些成分受到压力和 糖皮质激素及其对CD8+CTL反应产生的影响。