BCR signaling during B cell development and maintenance

B 细胞发育和维持期间的 BCR 信号传导

• 批准号: 6702282
• 负责人: KLAUS RAJEWSKY
• 金额: $ 47.25万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702282
• 关键词: BCR; signaling; during; cell; development

DESCRIPTION (provided by the applicant): A major determinant in the development, selection and differentiation of B lymphocytes is the B cell antigen receptor (BCR) whose antibody variable regions recognize antigen and whose signaling unit (the Igalpha/Beta heterodimer transmits signals into the interior of the cell. Signaling pathways activated by Igalpha/Beta cytoplasmic tails control the response of the cells to antigenic selection including tolerance induction by antigen to avoid autoimmunity and antibody responses to pathogens. BCR signaling also seems to be required for mature B cell survival. Signaling through the cytoplasmic tails of Igalpha/Beta requires phosphorylation of tyrosine-based activation motifs termed ITAMs. However, there is evidence mainly from work on cell lines that other conserved targets of phosphorylation in these tails including serine and threonine residues also contribute to signal transduction. The present proposal aims at defining the role of these residues in B cell development and activation in the in vivo context, using targeted mutagenesis in the mouse. We will similarly analyze the roles of the cytoplasmic tails in the maintenance of mature B cells and their interplay with B-cell activation factor mediated survival, using systems of inducible gene targeting. Knowledge about the control of B cell survival is critical for an understanding of B cell homeostasis and therapeutic intervention in B cell-mediated autoimmunity and B cell lymphoma growth. In a final part of the proposal, we will address to which extent the differentiation of B cells into the B-1 and B-2 subsets is driven by BCR specificities which are unequally distributed between the two subsets. B-1 cells are thought to play a major role in natural immune defense and to be prone to autoantibody production, whereas B-2 cells are the major players in adaptive antibody responses. We will use a genetic switch allowing the cells to switch in vivo from the expression of a B-I typical to a B-2-typical BCR and vice versa, to determine to which extent the B-1 and B-2 phenotypes represent distinct states of activation as opposed to being determined by distinct developmental programs. This will be complemented by an attempt to switch mature B-2 ceils to a B-1 phenotype by induced inactivation of SHP- 1 phosphatase whose inactivation in B cell progenitors leads to near-exclusive production of B- 1 cells

描述（由申请人提供）：B淋巴细胞开发，选择和差异化的主要决定因素是B细胞抗原受体（BCR），其抗体可变区域识别抗原区域且信号单位（Igalpha/beta Heterodimer传递信号均传递了细胞的响应/BETIS范围。抗原的选择包括抗原诱导自身免疫性和对病原体的抗体反应，而BCR信号的成熟也需要通过igalpha/beta的细胞质尾巴来进行。包括丝氨酸和苏氨酸残基在内的这些尾巴中的磷酸化也有助于信号转导。我们将使用诱导基因靶向系统类似地分析细胞质尾巴在维持成熟B细胞中的作用及其与B细胞活化因子介导的生存的相互作用。关于B细胞存活的控制的知识对于了解B细胞稳态和B细胞介导的自身免疫性和B细胞淋巴瘤生长的治疗干预至关重要。在该提案的最后一部分中，我们将解决B细胞在B-1和B-2子集中的分化在多大程度上由BCR特异性驱动的，BCR的特异性在两个子集之间不等。 B-1细胞被认为在天然免疫防御中起主要作用，并且容易产生自身抗体，而B-2细胞是自适应抗体反应的主要参与者。我们将使用遗传开关，允许细胞从典型的B-I的表达转换为B-2典型BCR，反之亦然，以确定B-1和B-2表型在多大程度上代表了不同的激活状态，而不是由不同的发展程序确定。通过将成熟的B-2天花板转换为B-1表型的尝试，通过诱导SHP-1磷酸酶的失活，其在B细胞祖细胞中的失活导致B-1细胞的产生几乎是排斥的产生，这将得到补充。