The fourth TCR signaling module, also involved in the formation of a stable immune synapse, leads to reorganization of the actin cytoskeleton. Without this process, integrin aggregation would not occur, interactions between the T cell and the APC would not stabilize, and in fact, T-cell activation would completely fail. A major component of this T-cell receptor signal is transduced by Vav, a GEF that activates Rho-family GTPases, including Cdc42. Like PLC-γand Itk, Vav is recruited to the site of receptor activation by interactions of the Vav PH domain with PIP3 and of the Vav SH2 domain with the LAT:Gads:SLP-76 scaffold complex (Fig. 7.24). When Cdc42 is activated by Vav, the GTP-bound Cdc42 induces a conformational change in the protein WASp (Wiskott– Aldrich syndrome protein), which is also recruited to the LAT:Gads:SLP-76 scaffold complex by binding to the small adaptor protein Nck. This active form of WASp binds to WIP, and together, these proteins recruit Arp2/3, leading to actin polymerization. The importance of this pathway is underscored by the fact that defects in WASp are the basis for the immunodeficiency disease Wiskott–Aldrich syndrome. Due to the widespread expression of WASp, individuals suffering from this disease have impairments in multiple immune cell types, all of which depend on WASp-dependent actin polymerization for their functions. One major defect in this disease is in T cell-dependent antibody responses, due to the requirement for actin polymerization to ensure effective interactions between CD4 T cells and B cells. Thus, the failure of WASpdeficient T cells to provide adequate ‘help’ to B cells most likely results from a defect in the formation of the immune synapse, which is normally required to ensure directed secretion of cytokines from the T cell onto the B-cell membrane (Fig. 7.25).
7-20 The logic of B-cell receptor signaling is similar to that of T-cell receptor signaling, but some of the signaling components are specific to B cells.
There are many similarities between signaling from T-cell receptors and signaling from B-cell receptors. As with the T-cell receptor, the B-cell receptor is composed of antigen-specific chains associated with ITAM-containing signaling chains, in this case Igα and Igβ (see Fig. 7.10). In B cells, three protein tyrosine kinases of the Src family—Fyn, Blk, and Lyn—are thought to be responsible for phosphorylation of the ITAMs (Fig. 7.26). These kinases associate with
Fig. 7.24 Recruitment of Vav to the LAT:Gads:SLP-76 complex induces activation of Cdc42, leading to actin polymerization. Left panel: vav, a guanine-nucleotide exchange factor (Gef) for the small GTpase cdc42, is recruited to the activated T-cell receptor (TcR) complex by binding via its ph domain to pip3 in the membrane and by binding to phosphorylated SLp-76. The small adaptor protein nck binds to an adjacent phosphorylated tyrosine on SLp-76 and recruits the inactive form of the protein WaSp. middle panel: vav activates cdc42, which binds to and activates WaSp. Right panel: active WaSp binds to Wip, recruiting arp2/3 and inducing actin polymerization. The importance of this pathway is illustrated by the discovery of WaSp as the protein encoded by the gene responsible for the human immunodeficiency disease Wiskott– aldrich syndrome.