BCR signaling during B cell development and maintenance

超出提供的空间。B细胞抗原受体(BCR)是B淋巴细胞发育、选择和分化的主要决定因素，它的抗体可变区识别抗原，其信号单位(IGOD_Heterodimer)将信号传递到细胞内部。IGOD_胞浆尾巴激活的信号通路控制细胞对抗原选择的反应，包括由抗原诱导的耐受，以避免自身免疫和抗体反应。BCR信号似乎也是成熟B细胞生存所必需的。通过Ig(x/_)胞质尾部的信号传递需要被称为ITAM的酪氨酸激活基序的磷酸化。然而，主要来自细胞系的证据表明，这些尾巴中的其他磷酸化靶点包括丝氨酸和苏氨酸残基也有助于信号转导。本提案旨在通过在小鼠中进行定向突变，确定这些残基在体内B细胞发育和激活中的作用。类似地，我们将使用诱导基因打靶系统，分析细胞质尾巴在维持成熟B细胞中的作用以及它们与B细胞激活因子介导的生存的相互作用。关于B细胞存活控制的知识对于理解B细胞稳态以及对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。在提案的最后部分，我们将阐述B细胞到B-1和B-2亚集的分化在多大程度上是由在这两个亚集之间不均匀分布的BCR特异性所驱动的。B-1细胞被认为在自然免疫防御中起主要作用，并且容易产生自身抗体，而B-2细胞是适应性抗体应答的主要参与者。我们将使用一个基因开关，允许细胞在体内从B-I典型的BCR表达切换到B-2典型的BCR表达，以确定B-1和B-2表型在多大程度上重新呈现不同的激活状态，而不是由不同的发育程序决定。此外，还将尝试通过诱导SHP-1磷酸酶失活来将成熟的B-2细胞转换为B-1表型。SHP-1磷酸酶在B细胞前体细胞中的失活会导致B-1细胞的近乎排他性生产。表演网站========================================Section End===========================================

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===========================================