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

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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.