MECHANISMS OF B CELL ACTIVATION BY CLASS II MHC AND CD40

II 类 MHC 和 CD40 激活 B 细胞的机制

• 批准号: 2667708
• 负责人: GAIL A. BISHOP
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2667708
• 关键词: B lymphocyte; CD40 molecule; MHC class II antigen; T lymphocyte; biological signal transduction; cell cell interaction; chimeric proteins; immunoglobulins; laboratory mouse; leukocyte activation /transformation; membrane proteins; polymerase chain reaction; protein structure function; protein tyrosine kinase; tissue /cell culture; transfection

B cell activation is a highly regulated process involving multiple different signals. The net effect of these interacting signal pathways is to determine the B cell response to recognition of antigen. A detailed understanding of how signal transducing molecules on B cells work is essential to understanding, and potentially controlling, B cell proliferation and antibody secretion. Thus, specifically targeted therapies for B cell hyperproliferative diseases, such as B cell malignancies, require an understanding of how B cell signaling pathways function and interact. The majority of B lymphocyte activation events involve specific binding of B cell membrane Ig to antigen, and interaction with T helper cells via both polymorphic and non-polymorphic transmembrane molecules. Nonspecific B cell activation signals can be provided by T cell-secreted lymphokines and nonpolymorphic T cell membrane molecules, such as CD40 ligand (CD40L) on activated T cells. However, it is our hypothesis that specific interactions with antigen prepare B cells to respond optimally to subsequent T cell-mediated signals, and specific interactions between T cell receptors and B cell MHC class II molecules preserve the specificity of T cell-B cell interactions. Our laboratory and others have demonstrated that class II MHC molecules preserve the specificity of T cell-B interactions. Our laboratory and others have demonstrated that class II MHC molecules deliver regulatory signals to B lymphocytes, and that these signals synergize with signals delivered by the binding of antigen to membrane ig. In addition, class II-mediated signals counteract antigen-mediated anergy signals, which may be a mechanism by which T cells stimulate B cell hyperproliferation in malignancy and autoimmune disease. More recently, we have obtained data indicating that signals delivered via class II cooperate with signals delivered to B cells by the binding of T cell CD40L B cell CD40. We thus believe that signals delivered by antigen and cognate interaction with T cells (i.e., signals delivered by binding of mig and MHC class II molecules) increase the effectiveness of CD40-mediated signals following T cell activation, and decrease the probability of inappropriate B cell activation through "bystander" effects. Thr proposed experiments will test determine the molecular basis of this interaction between signal receptors. Three major experimental approaches will be used to test our hypotheses. First, we will use recombinant DNA technology to produce alterations in the genes encoding MHC class II and CD40 molecules. Using B cell lines as models, we will introduce these altered genes and study the signaling function of the proteins they produce, to define a detailed relationship between structure and function for these signaling molecules. Second, we will use state-of=- the-art biochemical signaling assays to identify the intracellular events which result from signaling via class II MHC and CD40 molecules. Finally, we will perform in vitro and in vivo experiments examining the molecular mechanisms by which these signals cooperate in the regulation of B cell activation. The combination of these three approaches will yield a better understanding of how to manipulate athe process of B cell activation, through better understanding of the mechanism of, and interactions between the component parts of the process.

B细胞活化是一个高度调节的过程，涉及多个 不同的信号。 这些相互作用的信号通路的净效应是 以确定B细胞对抗原识别的应答。 详细 了解B细胞上的信号转导分子如何工作， 对理解和潜在控制B细胞至关重要 增殖和抗体分泌。 因此，专门针对 用于B细胞过度增殖性疾病如B细胞过度增殖性疾病的治疗 恶性肿瘤，需要了解如何B细胞信号通路 功能和互动。 大多数B淋巴细胞活化事件 涉及B细胞膜IG与抗原特异性结合，以及相互作用 与T辅助细胞通过多态性和非多态性跨膜 分子。 非特异性B细胞活化信号可由T 细胞分泌的淋巴因子和非多态性T细胞膜分子， 例如活化T细胞上的CD 40配体（CD 40 L）。 然而，这是我们的 假设与抗原特异性相互作用使B细胞 最佳地响应随后的T细胞介导的信号，和特异性 T细胞受体与B细胞MHC II类分子的相互作用 保持T细胞-B细胞相互作用的特异性。 本实验室 其他人已经证明II类MHC分子保留了 T细胞-B相互作用的特异性。 我们的实验室和其他实验室 证明II类MHC分子向B传递调节信号 淋巴细胞，并且这些信号与由淋巴细胞传递的信号协同作用。 抗原与膜的结合IG. 此外，II类介导的信号 抵消抗原介导的无反应性信号，这可能是一种机制， 其中T细胞刺激恶性肿瘤中的B细胞过度增殖， 自身免疫性疾病 最近，我们获得的数据表明， 通过II类传递的信号与传递到B细胞的信号协同作用 通过T细胞CD 40 L B细胞CD 40的结合。 因此，我们认为， 通过抗原和与T细胞的同源相互作用递送（即，信号 通过结合mig和MHCII类分子递送）增加了 T细胞活化后CD 40介导的信号的有效性，以及 降低不适当的B细胞活化的可能性， “旁观者”效应。 拟议的实验将测试确定 信号受体之间相互作用的分子基础。 三大 实验方法将被用来测试我们的假设。 一是 将使用重组DNA技术来改变基因 编码MHC II类和CD 40分子。 以B细胞系为模型， 将引入这些改变的基因，并研究这些基因的信号功能。 它们所产生的蛋白质，来定义结构之间的详细关系， 并为这些信号分子发挥作用。 其次，我们将使用state-of=- 现有技术的生物化学信号传导测定来鉴定细胞内事件 其由通过II类MHC和CD 40分子的信号传导产生。 最后， 我们将进行体外和体内实验， 这些信号协同调节B细胞的机制 activation. 这三种方法的结合将产生更好的效果。 了解如何操纵B细胞活化的逆转录过程， 通过更好地理解 过程的组成部分。