The role of CD4 in macrophage differentiation and function

描述(由申请人提供)：CD4分子在人类免疫系统和艾滋病毒的发病机制中发挥着重要作用。HIV发病机制中的一个关键因素是使用CD4分子作为细胞感染的主要受体。除了CD4T辅助细胞外，免疫系统中还有许多其他表达CD4的细胞，它们容易受到艾滋病毒的感染。单核细胞/巨噬细胞是HIV在感染者体内的主要目标之一，也是一个重要的、但知之甚少的宿主。除了允许艾滋病毒感染这些细胞外，CD4受体在单核/巨噬细胞的功能和发育中的作用尚不清楚。我们最近发现，单核/巨噬细胞上的CD4可以调节基因和细胞因子蛋白的表达以及T细胞的反应。我们有兴趣研究单核/巨噬细胞亚群中CD4分子的这一和其他角色和功能。我们在这一提议中的中心假设是，CD4通过调节控制细胞发育和其他免疫反应的因子的表达，在单核/巨噬细胞的分化和功能中发挥作用。这反过来又对HIV感染和理解感染细胞的单核/巨噬细胞库在疾病进展中具有重要意义。这项提案将重点解决这些问题，并将重点放在以下三个具体目标上：1.确定单核/巨噬细胞发育过程中CD4表达的调节机制。2.探讨CD_4在单核/巨噬细胞系分化发育过程中的作用(S)及其后果(S)。3.探讨CD_4分子对成熟单核/巨噬细胞功能的影响(S)。为了实现这一目标，我们将利用一种新的基于胚胎干细胞的系统，我们可以从基因上操纵和检测单核/巨噬细胞的分化和功能，这种细胞类型是人类造血发育中最早的细胞之一。总之，预计这些研究将阐明CD4在单核/巨噬细胞发育和/或功能中的潜在作用和重要性。此外，预计拟议的研究将使人们能够更全面地了解艾滋病毒感染这类细胞的后果。公共卫生相关性：本提案中描述的实验方法旨在解决核心假设，即CD4分子在免疫反应中具有比其对CD4T辅助细胞的能力更广泛的功能，进而在HIV发病机制中也具有更广泛的功能。这些研究将增加我们对CD4分子如何影响单核/巨噬细胞发育和免疫功能以及HIV如何影响这一过程的知识，从而加深我们对HIV感染机制和发病机制的理解。此外，在这些研究中使用胚胎干细胞，由于其高度可塑性、自我更新能力和可进行基因操作的能力，可能会使开发针对艾滋病毒和其他类似疾病的免疫替代治疗策略成为可能。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases.