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，其信号单位（Igalpha/Beta异源二聚体）将信号传递到细胞内部。由igα / β细胞质尾部激活的信号通路控制细胞对抗原选择的反应，包括抗原诱导耐受以避免自身免疫和对病原体的抗体反应。BCR信号似乎也是成熟B细胞存活所必需的。通过igα / β的细胞质尾部发出信号需要酪氨酸激活基序（ITAMs）的磷酸化。然而，主要来自细胞系研究的证据表明，这些尾部磷酸化的其他保守靶点，包括丝氨酸和苏氨酸残基，也有助于信号转导。目前的建议旨在确定这些残基在体内背景下B细胞发育和激活中的作用，在小鼠中使用靶向诱变。我们将类似地分析细胞质尾部在维持成熟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。了解B细胞存活的控制对于理解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子集在多大程度上是由两个子集之间不均匀分布的BCR特异性驱动的。B-1细胞被认为在自然免疫防御中起主要作用，易于产生自身抗体，而B-2细胞在适应性抗体反应中起主要作用。我们将使用一种基因开关，允许细胞在体内从B-1典型的BCR转换为B-2典型的BCR，反之亦然，以确定B-1和B-2表型在多大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。通过诱导SHP- 1磷酸酶失活，将成熟的B-2细胞转变为B-1表型，这种酶在B细胞祖细胞中的失活导致B-1细胞的产生