Investigating the role of Grb2, Dok-3, Cbl and dynein in antigen internalization to provide the second signal for B cell activation

研究 Grb2、Dok-3、Cbl 和动力蛋白在抗原内化中的作用，为 B 细胞激活提供第二个信号

• 批准号: 209007142
• 负责人: Dr. Selina Keppler
• 金额: --
• 依托单位: Lymphocyte Interaction Laboratory
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/209007142?language=en
• 关键词: Investigating; role; Grb2; Dok; Cbl

Activation of B cells requires two temporally separated signals: (I.) the ligation of the B cell receptor (BCR) with antigen, and (II.) a costimulatory signal, enabling the maximal activation of B cells, including proliferation, differentiation and antibody production. Antigen engagement of the BCR leads to the recruitment of an array of intracellular effectors and adaptors which mediate intracellular signalling ultimately resulting in antigen internalization into endosomes. Antigen within endosomes is processed, loaded onto MHC class II-molecules and presented on the B cell surface. MHC class II-antigen complexes recruit cognate CD4 T helper cells, which provide the second signal for B cell activation. Recently it became evident that invariant natural killer T cells (iNKT cells) and B cell intrinsic Toll-like receptor 9 (TLR9) engagement in endosomes can also provide the second signal. From these experiments it appears that the endosomal compartment plays a critical role in co-ordinating the combinatorial signals that govern the outcome of B cell activation. However, the molecular events underlying antigen delivery to endosomes is unclear. In this project, we will investigate the mechanisms for BCR-mediated antigen internalization to endosomal comparments, and in particular the role of the adaptor proteins Grb2 and Dok-3, the ubiquitin ligase Cbl and the microtubule motor protein dynein in this process. We will uncover how these molecules participate in the delivery of the second signal for activation either through CD4 T cells, iNKT cells or TLR9 ligation, and how this influences B cell fate in vivo. Results from this study will contribute to the understanding of the combinatorial signalling that underlies the activation of B cells during both, protective antibody responses and autoimmune diseases. Furthermore, this information is likely to represent a general mechanism to couple movement and internalization of numerous cell surface receptors.

B细胞的激活需要两个时间上分离的信号：（I.）B细胞受体（BCR）与抗原的连接，和（II.）共刺激信号，使B细胞的最大活化，包括增殖、分化和抗体产生。BCR的抗原接合导致细胞内效应子和衔接子阵列的募集，其介导细胞内信号传导，最终导致抗原内化到内体中。内体内的抗原被加工，加载到MHC II类分子上并呈递在B细胞表面上。MHC II类-抗原复合物募集同源的CD 4 T辅助细胞，其为B细胞活化提供第二信号。最近变得明显的是，不变的自然杀伤T细胞（iNKT细胞）和内体中的B细胞内在Toll样受体9（TLR 9）接合也可以提供第二信号。从这些实验看来，内体区室在协调控制B细胞活化结果的组合信号中起关键作用。然而，抗原递送至内体的分子事件尚不清楚。 在这个项目中，我们将研究BCR介导的抗原内化到内体室的机制，特别是衔接蛋白Grb 2和Dok-3，泛素连接酶Cbl和微管运动蛋白动力蛋白在这个过程中的作用。我们将揭示这些分子如何通过CD 4 T细胞、iNKT细胞或TLR 9连接参与第二激活信号的传递，以及这如何影响体内B细胞的命运。这项研究的结果将有助于理解的组合信号的基础上激活的B细胞在保护性抗体反应和自身免疫性疾病。此外，这一信息可能代表了一个一般的机制，耦合运动和内化的许多细胞表面受体。