Mechanisms of co-stimulatory molecule expression in DCs

描述（由申请人提供）：T细胞活化需要通过抗原呈递细胞（APC）上的MHC+抗原复合物与T细胞受体（TCR）接合而递送的主要信号。此外，由APC上的共刺激分子B7-1、B7-2和CD 40递送的次级信号对于T细胞活化也是必需的。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。微生物剂，如脂多糖（LPS），是DC功能的最重要的调节剂之一。LPS和其他微生物试剂与Toll样受体（TLR）的结合可导致DC上MHC和共刺激分子的细胞表面表达上调，以及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细胞活化所必需的。虽然许多最近的研究已经解决了在DC中控制MHC细胞表面表达所涉及的机制，但对在这些细胞中调节共刺激分子（CM）表面表达所涉及的机制知之甚少。本文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诱导的分子机制，最终决定细胞表面表达水平的CM B7-1，B7-2和CD 40在DC中。更好地理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。本文提出的研究的另一个关键目标是定义参与确定巨噬细胞和DC诱导的反应的功能特异性的分子机制，特别是那些与CM表达调控有关的机制。本申请的具体目的是：（1）DC中共刺激分子表达的转录控制：NF-κ B因子的作用;（2）转录后机制在调节DC中共刺激分子细胞表面表达中的作用; 3）参与确定巨噬细胞和DC的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.