Glucocorticoid/Stress Effects on Dendritic Cell Function

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的皮质酮增加影响CD 8+细胞毒性T淋巴细胞（CTL）反应的细胞和分子机制。一个有效的和强大的CD 8 + CTL淋巴细胞反应是必要的成功防御许多疾病的免疫抵抗，特别是病毒感染和一些肿瘤。这种反应的效率和稳健性绝对依赖于树突细胞的有效功能。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，以成功激活CD 8 + T细胞。这些关键功能的任何损害都会破坏CD 8 + T细胞反应。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CD 8 + T细胞免疫抑制的了解是不完整的。对抗原加工和呈递以及树突状细胞功能所涉及的细胞和分子过程的了解为剖析应激相关免疫功能调节的机制提供了独特的机会。因此，我们目前的目标是利用这些知识来检验这一假设，即应激和应激相关的皮质酮增加调节树突状细胞功能。具体而言，我们解决这些功能与树突状细胞的成熟，和树突状细胞的处理和提出MHC I类限制性抗原和诱导抗原特异性CTL的能力。这些研究特别关注抗原呈递的直接和交叉呈递途径，以及确保保护性CTL应答所需的树突状细胞的活化和成熟。为实现这一目标，提出了三个具体目标：（I）确定皮质酮对MHC I类抗原加工和呈递的直接途径的亚细胞作用机制;（II）确定糖皮质激素和应激对体外和体内交叉呈递的影响;（III）研究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呈递和成熟的影响，是了解应激诱导的糖皮质激素影响天然免疫和疫苗接种引起的免疫发展的机制的关键环节。在这个项目完成后，我们将期望已经确定了那些关键的树突状细胞功能的组件，这些组件受到压力和糖皮质激素的影响，以及对CD 8 + CTL应答产生的影响。

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.