The role of CD4 in macrophage differentiation and function

项目摘要。 CD 4分子在人类免疫系统和HIV的发病机制中具有重要作用。 HIV发病机制中的一个关键因素是使用CD 4分子作为细胞感染的主要受体。 除了CD 4 + T辅助细胞，免疫系统中还有许多其他表达CD 4的细胞， 容易感染艾滋病病毒。主要目标之一，也是一个重要的和鲜为人知的 在受感染个体中HIV的储存库是单核细胞/巨噬细胞。除了允许艾滋病毒感染 在这些细胞中，CD 4受体在单核细胞/巨噬细胞的功能和发育中的作用不是 知道的 我们最近已经确定，单核细胞/巨噬细胞上的CD 4的连接调节基因， 细胞因子蛋白表达以及T细胞应答。我们有兴趣研究这个和其他角色， 单核细胞/巨噬细胞亚群上的CD 4分子的功能。我们的核心假设是 提出CD 4通过调节单核细胞/巨噬细胞的分化和功能， 控制细胞发育和其他免疫反应的因子的表达。这反过来又使 在HIV感染和单核细胞/巨噬细胞库的理解的重要影响， 感染的细胞在疾病进展中的作用本提案将侧重于解决这些问题，并将侧重于 三个具体目标： 1.确定单核细胞/巨噬细胞发育过程中调节CD 4表达的机制。 2.确定单核细胞/巨噬细胞谱系中CD 4表达的功能和后果 分化与发展。 3.确定CD 4分子对成熟单核细胞/巨噬细胞功能的作用。 为了实现这一目标，我们将利用一种新的胚胎干细胞为基础的系统，我们可以遗传操纵 并检查单核细胞/巨噬细胞的分化和功能，从一种细胞类型，这是最早的， 人类造血发育总之，预计这些研究将阐明 CD 4在单核细胞/巨噬细胞发育和/或功能中的潜在作用和重要性。进一步应 预计拟议的研究将使人们能够更全面地了解 艾滋病病毒感染在这种细胞类型。

Project Summary. The CD4 molecule has an important role in the human immune system and in the pathogenesis of HIV. A key factor in HIV pathogenesis is the use of the CD4 molecule as the primary receptor for cellular infection. In addition to CD4+ T helper cells, there are numerous other cells of the immune system that express CD4 that are susceptible to infection by HIV. One of the primary targets and an important and poorly understood reservoir for HIV in an infected individual are monocytes/ macrophages. Other than allowing HIV infection of these cells, the role of the CD4 receptor in the function and development of monocyte/macrophages is not known. We have recently determined that ligation of CD4 on monocytes/ macrophages modulates gene and cytokine protein expression as well as T cell responses. We are interested in examining this and other roles and functions of the CD4 molecule on the monocyte/ macrophage cell subset. Our central hypothesis in this proposal is that CD4 has a role in monocyte/ macrophage differentiation and function by modulating the expression of factors that control cellular development and other immune responses. This, in turn, has important implications in HIV infection and the understanding of the monocyte/ macrophage reservoir of infected cells in disease progression. This proposal will focus on addressing these issues and will focus on the following three Specific Aims: 1. To determine the mechanisms regulating CD4 expression during monocyte/ macrophage development. 2. To determine the function(s) and consequence(s) of CD4 expression during monocyte/ macrophage lineage differentiation and development. 3. To determine the role(s) of the CD4 molecule on mature monocyte/ macrophage function. To achieve this, we will utilize a novel embryonic stem cell-based system that we can genetically manipulate and examine monocyte/ macrophage differentiation and function from a cell type that is among the earliest in human hematopoietic development. In summary, it is anticipated that these studies will shed light on the potential roles and importance of CD4 in monocyte/macrophage development and/or function. Further, it is anticipated that the proposed studies will allow a more comprehensive understanding of the consequences of HIV infection in this cell type.