The role of CD4 in macrophage differentiation and function

描述（由申请人提供）：CD4分子在人体免疫系统和HIV发病机制中具有重要作用。HIV发病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CD4+ T辅助细胞外，免疫系统中还有许多其他表达CD4的细胞易受HIV感染。单核细胞/巨噬细胞是HIV感染个体的主要靶点之一，也是HIV感染的重要储存库。除了允许HIV感染这些细胞外，CD4受体在单核细胞/巨噬细胞的功能和发育中的作用尚不清楚。我们最近已经确定，单核细胞/巨噬细胞上的CD4结扎调节基因和细胞因子蛋白表达以及T细胞反应。我们有兴趣研究CD4分子在单核细胞/巨噬细胞亚群中的作用和功能。我们的中心假设是CD4通过调节控制细胞发育和其他免疫反应的因子的表达，在单核细胞/巨噬细胞的分化和功能中起作用。反过来，这对HIV感染和理解疾病进展中感染细胞的单核细胞/巨噬细胞库具有重要意义。这一建议将重点解决这些问题，并将围绕以下三个具体目标：探讨单核/巨噬细胞发育过程中CD4表达的调控机制。2. 目的：探讨单核/巨噬细胞谱系分化和发育过程中CD4表达的功能和后果。3. 确定CD4分子在成熟单核/巨噬细胞功能中的作用。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查单核细胞/巨噬细胞的分化和功能，这是人类造血发育中最早的细胞类型之一。总之，预计这些研究将揭示CD4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。此外，预计拟议的研究将使人们更全面地了解艾滋病毒感染在这种细胞类型中的后果。公共卫生相关性：本提案中描述的实验方法旨在解决CD4分子在免疫反应中具有更广泛的功能的中心假设，并通过扩展在HIV发病机制中，而不是其对CD4+ T辅助细胞的能力。这些研究将增加我们对CD4分子如何影响单核细胞/巨噬细胞发育和免疫功能以及HIV如何影响这一过程的认识；因此，增加了我们对HIV感染和发病机制的理解。此外，在这些研究中使用胚胎干细胞，由于其高可塑性、自我更新能力和基因操纵能力，可能允许开发针对艾滋病毒和其他类似疾病的免疫替代治疗策略。

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.