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: 6601098
• 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/6601098
• 关键词: B cell receptor; B lymphocyte; biological signal transduction; cell differentiation; gene rearrangement; gene targeting; genetically modified animals; immunoglobulin genes; laboratory mouse; leukocyte activation /transformation; protein sequence; serine; threonine; tyrosine

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（由申请方提供）：B淋巴细胞发育、选择和分化的主要决定因素是B细胞抗原受体（BCR），其抗体可变区识别抗原，其信号传导单位（Igalpha/β异源二聚体）将信号传递到细胞内部。由Igalpha/β胞质尾激活的信号传导途径控制细胞对抗原选择的应答，包括抗原诱导耐受以避免自身免疫和对病原体的抗体应答。BCR信号传导似乎也是成熟B细胞存活所必需的。通过Igal α/β的胞质尾的信号传导需要基于酪氨酸的激活基序（称为ITAM）的磷酸化。然而，有证据表明，主要来自细胞系的工作，其他保守的磷酸化目标，在这些尾巴，包括丝氨酸和苏氨酸残基也有助于信号转导。本建议的目的是定义这些残基的作用，在B细胞的发展和激活在体内的情况下，在小鼠中使用靶向诱变。我们将同样地分析细胞质尾在维持成熟B细胞中的作用，以及它们与B细胞活化因子介导的存活的相互作用，使用诱导基因靶向系统。有关控制B细胞存活的知识对于了解B细胞稳态和B细胞介导的自身免疫和B细胞淋巴瘤生长的治疗干预至关重要。在提案的最后一部分，我们将讨论B细胞分化为B-1和B-2亚群在多大程度上是由BCR特异性驱动的，BCR特异性在两个亚群之间分布不均匀。B-1细胞被认为在天然免疫防御中起主要作用并且易于产生自身抗体，而B-2细胞是适应性抗体应答中的主要参与者。我们将使用遗传开关，使细胞在体内从典型的B-I表达转换为典型的B-2表达，反之亦然，以确定B-1和B-2表型在何种程度上代表不同的激活状态，而不是由不同的发育程序决定。这将通过尝试通过诱导SHP- 1磷酸酶的失活将成熟B-2细胞转换为B-1表型来补充，SHP- 1磷酸酶在B细胞祖细胞中的失活导致B- 1细胞的几乎排他性的产生