Mechanisms of co-stimulatory molecule expression in DCs

描述(由申请人提供)：T细胞激活需要通过抗原呈递细胞(APC)上的MHC+抗原复合体与T细胞受体(TCR)接触而传递的主要信号。此外，共刺激分子B7-1、B7-2和CD40在APC上传递的二级信号也是T细胞激活所必需的。在APC中，只有树突状细胞(DC)被认为能够激活初始T淋巴细胞。脂多糖(LPS)等微生物制剂是DC功能最重要的调节因子之一。脂多糖和其他微生物因子结合Toll样受体(TLRs)可上调DC表面MHC和共刺激分子的表达，并导致炎性细胞因子的分泌。这个过程，通常被称为DC“成熟”，被认为是启动生产性T细胞激活的关键。虽然最近的许多研究都涉及到DC中MHC细胞表面表达的调控机制，但对这些细胞中共刺激分子(CM)表面表达的调控机制知之甚少。这里提出的研究的目标是帮助理解免疫调节的这一关键方面。为此，我们将研究脂多糖诱导的分子机制，最终决定DC表面CMS B7-1、B7-2和CD40的表达水平。更好地了解这些关键机制可能会为在治疗环境中调节这些分子的表达提供见解。这项研究的另一个关键目标是确定巨噬细胞和DC诱导的反应的功能特异性所涉及的分子机制，特别是与CM表达调控有关的机制。这一应用的具体目的是：(1)对DC中共刺激分子表达的转录调控：核因子-kB因子的作用；(2)转录后机制在调节DC共刺激分子细胞表面表达中的作用；3)参与决定巨噬细胞和DC功能特异性的分子机制：CM表达的调节。

DESCRIPTION (provided by applicant): T cell activation requires a primary signal delivered by engagement of the T cell receptor (TCR) by MHC+ antigen complexes on antigen-presenting cells (APCs). In addition, a secondary signal delivered by the co-stimulatory molecules B7-1, B7-2 and CD40 on APCs, is also necessary for T cell activation. Amongst APCs, only dendritic cells (DCs) are thought to be capable of activating naive T lymphocytes. Microbial agents, such as lipopolysaccaride (LPS), are amongst the most important regulators of DC function. Engagement of Toll-like receptors (TLRs) by LPS and other microbial agents can lead to upregulation of cell surface expression of both MHC and co-stimulatory molecules on DCs, and the secretion of inflammatory cytokines. This process, often referred to as DC "maturation", is thought to be essential for initiating productive T cell activation. While many recent studies have addressed mechanisms involved in controlling MHC cell surface expression in DCs, little is known about mechanisms involved in regulating co-stimulatory molecule (CM) surface expression in these cells. The goal of studies proposed here is to help understand this key aspect of immune regulation. To this end, we will investigate LPS-induced molecular mechanisms that eventually determine cell surface expression levels of the CMs B7-1, B7-2 and CD40 in DCs. A better understanding of these crucial mechanisms may provide insights for modulating expression of these molecules in therapeutic settings. An additional key goal of studies proposed here is to define molecular mechanisms involved in determining functional specificity of macrophage and DC-induced responses, in particular, those pertaining to regulation of CM expression. The specific aims of this application are: (1) Transcriptional control of co-stimulatory molecule expression in DCs: role of NF-kB factors; (2) The role of post-transcriptional mechanisms in regulating co-stimulatory molecule cell surface expression in DCs; 3) Molecular mechanisms involved in determining functional specificity of macrophages and DCs: regulation of CM expression.