Glucocorticoid/Stress Effects on Dendritic Cell Function

有大量的证据表明，心理应激诱导的，神经内分泌介导的调节， 记忆功能该计划的长期目标是确定细胞和分子机制 心理应激及其相关的皮质酮增加影响CD 8+细胞毒性T细胞 淋巴细胞（CTL）反应。一个有效和强大的CD 8 + CTL淋巴细胞反应是必要的， 成功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鲁棒性绝对取决于有效的 树突状细胞的功能。树突状细胞必须在正确的时间加工和呈递足够的抗原， 在正确的位置成功激活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，了解压力/皮质酮介导的抑制， 如果不了解应激/皮质酮对CD 8 + T细胞免疫的影响， 树突状细胞了解抗原加工中涉及的细胞和分子过程， 树突状细胞的功能提供了一个独特的机会，剖析机制， 应激相关的免疫功能调节。因此，我们目前的目标是利用这些知识， 为了验证压力和压力相关的皮质酮增加调节树突状细胞的假设， 功能具体来说，我们解决了与树突状细胞成熟相关的功能，以及树突状细胞的能力。 树突状细胞处理和呈递MHC I类限制性抗原并诱导抗原特异性CTL。 这些研究特别关注抗原呈递的直接和交叉呈递途径， 对树突状细胞的激活和成熟的影响，这是确保保护性CTL应答所必需的。到 为了实现这一目标，提出了三个具体目标：（I）确定亚细胞机制， 皮质酮对MHC I类抗原加工和呈递的直接途径的作用;（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） 确定糖皮质激素和应激对体外和体内树突状细胞成熟和功能的影响， vivo.这项研究的基本原理是，了解皮质酮的影响， 对树突状细胞抗原呈递和成熟的强调是理解 应激诱导的糖皮质激素影响天然来源的 免疫力和疫苗接种引起的免疫力。在这个项目完成后，我们将期待 已经确定了那些受压力影响的关键树突细胞功能的组成部分， 糖皮质激素和由此产生的对CD 8 + CTL应答的产生的影响。

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.