CD83 Regulation of Lymphocyte Development and Function

描述（由申请方提供）：淋巴细胞是细胞和体液免疫的中心介质，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。淋巴细胞功能和与树突状细胞的相互作用通过介导细胞间通讯、产生跨膜信号并指导淋巴细胞发育和组织内定位的细胞表面分子来调节。异常的淋巴细胞和树突状细胞功能导致免疫缺陷、自身免疫性疾病、年龄相关的免疫缺陷和恶性肿瘤。这些研究的目的是检查CD 83的功能，CD 83是一种细胞表面受体，我们首先将其鉴定为主要由人类树突状细胞表达的免疫球蛋白超家族的成员。基于我们已经产生的CD 83缺陷（CD 83-/-）小鼠的显著表型，CD 83作为T淋巴细胞选择和/或谱系定型的必需受体发挥功能。因此，CD 83参与独特地代表了胸腺中CD 4 + T细胞发育的新调节步骤，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CD 83与细胞外配体结合，这些配体告知发育中和成熟的淋巴细胞体内的细胞外微环境。这些信号可以调节外周中的淋巴细胞活化和存活，从而调节细胞和体液免疫应答。三个具体的目的是为了验证这一假设，并进一步了解CD 83如何调节正常淋巴细胞的发育和功能。具体目标1将确定CD 83如何在体内和体外调节胸腺细胞发育。具体目标2将确定CD 83是否以及如何调节外周淋巴细胞存活。在具体目标3中，我们将通过鉴定和表征小鼠胸腺细胞表达的CD 83配体来确定CD 83与细胞外配体的结合是否在体内调节淋巴细胞发育和功能。由于CD 83的表达为辅助性T细胞的发育提供了一个重要的调节检查点，因此了解其功能可能为调节体液免疫和治疗免疫缺陷、自身免疫和恶性肿瘤提供机制

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