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MHC+抗原复合物在抗原呈递细胞（apc）上结合T细胞受体（TCR）传递主要信号。此外，由apc上的共刺激分子B7-1、B7-2和CD40传递的二次信号也是T细胞活化所必需的。在apc中，只有树突状细胞（dc）被认为能够激活幼稚T淋巴细胞。微生物制剂，如脂多糖（LPS），是DC功能最重要的调节因子之一。脂多糖和其他微生物制剂参与toll样受体（TLRs）可导致dc上MHC和共刺激分子的细胞表面表达上调，以及炎症细胞因子的分泌。这个过程，通常被称为DC“成熟”，被认为是启动生产性T细胞激活的必要条件。虽然最近的许多研究都涉及到控制dc中MHC细胞表面表达的机制，但对这些细胞中调节共刺激分子（CM）表面表达的机制知之甚少。这里提出的研究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lps诱导的最终决定DCs中CMs B7-1、B7-2和CD40细胞表面表达水平的分子机制。更好地了解这些关键机制可能为在治疗环境中调节这些分子的表达提供见解。这里提出的研究的另一个关键目标是确定巨噬细胞和dc诱导反应的功能特异性的分子机制，特别是与CM表达调节有关的分子机制。该应用的具体目的是：(1)DCs中共刺激分子表达的转录控制：NF-kB因子的作用；(2)转录后机制在调控dc共刺激分子细胞表面表达中的作用；3)决定巨噬细胞和dc功能特异性的分子机制：CM表达的调控。

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.