CD83 Regulation of Lymphocyte Development and Function

CD83 对淋巴细胞发育和功能的调节

• 批准号: 7117861
• 负责人: THOMAS F TEDDER
• 金额: $ 27.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117861
• 关键词: CD antigens; T lymphocyte; athymic mouse; biological signal transduction; cell age; cell differentiation; cell growth regulation; cell surface receptors; dendritic cells; extracellular; gene expression; genetic models; genetically modified animals; helper T lymphocyte; immune response; immunogenetics; in situ hybridization; laboratory mouse; leukocyte activation /transformation; ligands; polymerase chain reaction; protein structure function; receptor binding; receptor expression; thymus

DESCRIPTION (provided by applicant): Lymphocytes are the central mediators of cellular and humoral immunity, but they depend on dendritic and other reticuloendothelial cells during development and for the generation of acquired immunity. Lymphocyte function and interactions with dendritic cells are regulated through cell-surface molecules that mediate intercellular communication, generate transmembrane signals, and direct lymphocyte development and localization within tissues. Aberrant lymphocyte and dendritic cell functions contribute to immunodeficiencies, autoimmune conditions, age-related defects in immunity, and malignancies. The aim of these studies is to examine the function of CD83, a cell-surface receptor that we first identified as a member of the immunoglobulin superfamily predominantly expressed by dendritic cells in humans. Based on the remarkable phenotype of CD83-deficient (CD83-/-) mice that we have generated, CD83 functions as an essential receptor for T lymphocyte selection and/or lineage commitment. Thus, CD83 engagement uniquely represents a new regulatory step for CD4+ T cell development in the thymus, but is likely to have additional functions in the immune system. We propose that CD83 expressed by mouse dendritic and thymic epithelial cells binds extracellular ligand(s), which inform developing and mature lymphocytes of their extracellular microenvironment in vivo. These signals may regulate lymphocyte activation and survival in the periphery and thereby regulate cellular and humoral immune responses. Three specific aims are designed to test this hypothesis and to further our knowledge of how CD83 regulates normal lymphocyte development and function. Specific aim 1 will determine how CD83 regulates thymocyte development in vivo and in vitro. Specific aim 2 will determine whether and how CD83 regulates peripheral lymphocyte survival. In specific aim 3, we will determine whether CD83 binding to extracellular ligand(s) regulates lymphocyte development and function in vivo by identifying and characterizing CD83 ligands expressed by mouse thymocytes. Since CD83 expression provides an important regulatory checkpoint for helper T cell development, understanding its function may provide mechanisms for modulating humoral immunity and for the treatment of immunodeficiency, autoimmunity and malignancies

描述(申请人提供)：淋巴细胞是细胞和体液免疫的中心媒介，但它们在发育过程中依赖于树突状细胞和其他网状内皮细胞，并产生获得性免疫。淋巴细胞的功能和与树突状细胞的相互作用是通过细胞表面分子来调节的，这些分子介导细胞间的通讯，产生跨膜信号，并指导淋巴细胞的发育和在组织中的定位。异常的淋巴细胞和树突状细胞功能导致免疫缺陷、自身免疫状况、年龄相关的免疫缺陷和恶性肿瘤。这些研究的目的是研究CD83的功能，CD83是一种细胞表面受体，我们首次确定它是免疫球蛋白超家族的成员，主要由人类树突状细胞表达。基于我们建立的CD83缺陷(CD83-/-)小鼠的显著表型，CD83作为T淋巴细胞选择和/或谱系承诺的必要受体发挥作用。因此，CD83的参与代表了胸腺中CD4+T细胞发育的一个新的调节步骤，但可能在免疫系统中具有额外的功能。我们认为，小鼠树突状细胞和胸腺上皮细胞表达的CD83与细胞外配体(S)结合，从而向发育中和成熟的淋巴细胞提供体内细胞外微环境的信息。这些信号可能调节外周淋巴细胞的激活和存活，从而调节细胞和体液免疫反应。我们设计了三个具体的目标来检验这一假说，并进一步了解CD83如何调节正常的淋巴细胞发育和功能。具体目标1将确定CD83如何在体内和体外调节胸腺细胞的发育。具体目标2将确定CD83是否以及如何调节外周淋巴细胞存活。在具体目标3中，我们将通过鉴定和鉴定小鼠胸腺细胞表达的CD83配体，来确定CD83与细胞外配体(S)结合是否在体内调节淋巴细胞的发育和功能。由于CD83的表达为辅助T细胞的发育提供了一个重要的调节检查点，了解它的功能可能会为调节体液免疫以及治疗免疫缺陷、自身免疫和恶性肿瘤提供机制