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: 6840820
• 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/6840820
• 关键词: BCR; signaling; during; cell; development

EXCEED THE SPACE PROVIDED. 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 Igod_ he- terodimer) transmits signals into the interior of the cell. Signaling pathways activated by Igod_ 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 Ig(x/_ requires phosphorylation of tyrosine-based ac- tivation motifs termed ITAMs. However, there is evidence mainly from work on cell lines that other con- served targets of phosphorylation in these tails including serine and threonine residues also contribute to sig- nal 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 auto- immunity 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 re- sponses. 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 re- present 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。B淋巴细胞的发育、选择和分化中的主要决定因素是B细胞抗原受体（BCR），其抗体可变区识别抗原，并且其信号传导单元（Igod_异二聚体）将信号传递到细胞内部。Igod_胞质尾激活的信号通路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IG（x/_）的胞质尾部的信号传导需要称为ITAM的基于酪氨酸的活化基序的磷酸化。然而，主要来自细胞系研究的证据表明，这些尾中的其他保守的磷酸化靶点（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。我们将类似地分析胞质尾在维持成熟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。关于控制B细胞存活的知识对于理解B细胞稳态和在B细胞介导的自身免疫和B细胞淋巴瘤生长中的治疗干预是至关重要的。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，允许细胞在体内从B-I-典型BCR的表达切换到B-2-典型BCR的表达，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细胞的几乎排他性产生。 性能现场=