FUNCTION OF CD19 IN B CELL DEVELOPMENT & DIFFERENTIATION

CD19 在 B 细胞发育中的功能

• 批准号: 2637332
• 负责人: ROBERT C RICKERT
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2637332
• 关键词: B cell receptor; B lymphocyte; CD antigens; antibody formation; biological signal transduction; cell differentiation; developmental immunology; flow cytometry; gene mutation; genetically modified animals; immunocytochemistry; laboratory mouse; leukocyte activation /transformation

DESCRIPTION (Adapted from the Investigator's Abstract): Antigen receptor-mediated signaling is the key determinant governing B lymphocyte activation, differentiation or death. Molecules that modulate signals through the B cell receptor (BCR) can thus be instrumental in determining B cell fate. Much attention has been given to intracellular intermediates acting downstream of the BCR. This proposal addresses the biological role of the B cell "co-receptor" CD19 which, in the appropriate context, can augment BCR-mediated B cell activation and proliferation. The investigator has found that CD19--deficient mice are impaired in B cell lymphopoiesis and in responding to T cell-dependent antigens, and he proposes to determine the molecular basis for these defects in the context of CD19 association with the BCR and the CD19/CD21 (complement receptor 2)/CD81 complexes. In Aim 1 the role of CD19 in early B cell development will be examined, focusing on developmental checkpoints regulated by pre-BCR or BCR signaling. This involves a comparative analysis of CD19-/- and wildtype mice, which will be refined by the use of pre-BCR mutant mice and immunoglobulin transgenic mice bred onto the CD19 null background. As CD19-/- mice exhibit a severe reduction in B-1 (formerly ly-1) B cells, in Aim 1b they will determine whether this deficiency is mainly attributed to inefficient generation, expansion or maintenance of this important subpopulation of B cells. Aim 2 addresses the role of CD19 in the recognition of and activation by foreign antigen. It will be determined whether CD19 acts as the signaling moiety of the CD19/CD21/CD81 complex, which is known to synergize with surface immunoglobulin in the co-recognition of opsonized (C3d-bearing) foreign antigen. Immunizations will be accompanied by flow cytometric and immunohistochemical techniques to assess B cell differentiation, migration and survival. Aim 3 will delineate the dual roles of CD19 as both a member of the CD19/CD21/CD81 complex and also as an elementary component of the BCR. This will be accomplished by complementation of the CD19 null mutation with transgenes encoding modified CD19 molecules which associate exclusively with the BCR or CD19/CD21/CD81 complexes. This genetic approach will assess the relative contribution of CD19 to the function of these crucial signaling complexes in effecting B cell differentiation and antibody production.

描述（改编自研究者摘要）：抗原 受体介导的信号传导是控制B淋巴细胞的关键决定因素 激活、分化或死亡。 调节信号的分子 通过B细胞受体（BCR）的免疫反应可用于测定B 细胞命运 细胞内中间体已引起人们的极大关注 作用于BCR的下游。 该提案涉及生物学作用 B细胞“共受体”CD 19的表达，在适当的情况下， 增强BCR介导的B细胞活化和增殖。 研究者 发现CD 19缺陷小鼠的B细胞淋巴细胞生成受损， 在响应T细胞依赖性抗原，他提出，以确定 这些缺陷的分子基础在CD 19与 BCR和CD 19/CD 21（补体受体2）/CD 81复合物。 目标1 将研究CD 19在早期B细胞发育中作用，重点是 由前BCR或BCR信号调节的发育检查点。 这 涉及CD 19-/-和野生型小鼠的比较分析， 通过使用前BCR突变小鼠和免疫球蛋白转基因小鼠进行改进， 在CD 19空白背景下繁殖。 由于CD 19-/-小鼠表现出严重的 B-1（以前为ly-1）B细胞减少，在目标1 B中，他们将确定 这一缺陷是否主要归因于发电效率低下， 扩增或维持这一重要的B细胞亚群。 目的2 阐述了CD 19在识别和激活外源基因中的作用。 抗原的 将确定CD 19是否充当CD 19的信号传导部分。 已知CD 19/CD 21/CD 81复合物与表面活性剂协同作用， 免疫球蛋白在共识别调理（C3 d-轴承）外来 抗原的 免疫接种将伴随流式细胞术和 免疫组织化学技术评估B细胞分化、迁移 和生存 目的3将描述CD 19的双重作用，作为一个成员， CD 19/CD 21/CD 81复合物的基本成分， BCR。 这将通过CD 19无效突变的互补来实现 用编码修饰的CD 19分子的转基因， 与BCR或CD 19/CD 21/CD 81复合物。 这种遗传学方法将评估 CD 19对这些关键信号传导功能的相对贡献 复合物影响B细胞分化和抗体产生。