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: 7098380
• 负责人: ROBERT H. BONNEAU
• 金额: $ 36.18万
• 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/7098380
• 关键词: antigens; corticosterone; dendritic cells; glucocorticoids; stress

DESCRIPTION (provided by applicant): There is substantial evidence for psychological stress-induced, neuroendocrine-mediated modulation of immune 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.

描述(由申请人提供)：有大量证据表明，心理应激诱导的、神经内分泌介导的免疫功能调节。该计划的长期目标是确定心理应激及其相关皮质酮增加影响CD8+细胞毒性T淋巴细胞(CTL)反应的细胞和分子机制。有效和强大的CD8+CTL淋巴细胞反应对于成功防御许多免疫抵抗的疾病是必要的，特别是病毒感染和一些肿瘤。这种反应的效率和稳定性完全依赖于树突状细胞的有效功能。树突状细胞必须在正确的时间和正确的位置处理和呈递足够的抗原，才能成功激活CD8+T细胞。这些关键功能的任何损害都会破坏CD8+T细胞的反应。因此，如果不了解应激/皮质酮对树突状细胞的影响，对应激/皮质酮介导的CD8+T细胞免疫抑制的理解是不完整的。对参与抗原处理和提呈的细胞和分子过程以及树突状细胞功能的了解为剖析与应激相关的免疫功能调节机制提供了独特的机会。因此，我们目前的目标是利用这一知识来检验应激和应激相关的皮质酮增加调制树突状细胞功能的假设。具体地说，我们讨论了与树突状细胞成熟相关的功能，以及树突状细胞处理和呈递MHC类L限制性抗原和诱导抗原特异性CTL的能力。这些研究特别侧重于抗原递呈的直接和交叉递呈途径，以及确保保护性CTL反应所需的树突状细胞的激活和成熟。为了实现这一目标，我们提出了三个具体的目标：(I)确定皮质酮在MHC-I类抗原加工和递呈的直接途径上的亚细胞机制；(Ii)确定糖皮质激素和应激对体外和体内交叉递呈的影响；(Iii)确定糖皮质激素和应激对树突状细胞成熟和功能的影响。这项研究的基本原理是，了解皮质酮和应激对树突状细胞抗原提呈和成熟的影响是理解应激诱导的糖皮质激素影响自然衍生免疫和疫苗免疫的机制的关键环节。在这个项目完成时，我们将有望确定那些关键的树突状细胞功能的成分，这些成分受到应激和糖皮质激素的影响，以及由此对CD8+CTL反应产生的影响。