BCR signaling during B cell development and maintenance

B淋巴细胞的发育、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，并且其信号传导单位（Igod_ he- terodimer）将信号传递到细胞内部。Igod_细胞质激活的信号通路 尾部控制细胞对抗原选择的反应，包括抗原诱导的耐受性， 自身免疫和对病原体的抗体反应。BCR信号似乎也是成熟B 细胞存活通过IG（x/_）的胞质尾部的信号传导需要酪氨酸基ac-磷酸化。 激活基序称为ITAM。然而，有证据表明，主要是从工作的细胞系，其他CON- 在这些尾部中的磷酸化作用靶点，包括丝氨酸和苏氨酸残基，也有助于信号转导。 终末转导本提案旨在确定这些残基在B细胞发育中的作用， 在小鼠中使用靶向诱变在体内环境中激活。我们将类似地分析角色 成熟B细胞维持中的胞质尾区及其与B细胞活化因子的相互作用- 介导的生存，使用诱导基因靶向系统。关于控制B细胞存活的知识 是理解B细胞稳态和治疗干预B细胞介导的自体免疫的关键。 免疫和B细胞淋巴瘤生长。在提案的最后一部分，我们将讨论在何种程度上 B细胞分化为B-1和B-2亚群是由BCR特异性驱动的， 分布在两个子集之间。B-1细胞被认为在天然免疫防御中起主要作用， 容易产生自身抗体，而B-2细胞是适应性抗体重新产生的主要参与者。 海绵。我们将使用一个基因开关，允许细胞在体内从表达B-I- 典型BCR与B-2-典型BCR之间的关系，反之亦然，以确定B-1和B-2表型在多大程度上与典型BCR之间的关系。 呈现不同的激活状态，而不是由不同的发育程序决定。这 将通过尝试将成熟B-2细胞转化为B-1表型来补充， SHP- 1磷酸酶，其在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。

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.