Left panel: prior to T-cell receptor (TcR) signaling, the integrin Lfa-1 is present on the T-cell membrane in a low-affinity conformation that binds weakly to icam-1 on antigen-presenting-cells. middle panel: following TcR signaling, the adaptor protein adap is recruited to the LaT:Gads:SLp-76 complex by an interaction between tyrosine-phosphorylated adap and the Sh2 domain of SLp-76. adap then recruits a complex of SKap and Riam (Rap1-GTpinteracting adaptor molecule), activating the small GTpase Rap1. Right panel: active Rap1 induces aggregation of Lfa-1 and a conformational change in Lfa-1 that leads to high-affinity binding to icam-1.
Yet another important function of activated Akt is to stimulate the mTOR (mammalian target of rapamycin) pathway, a key regulator of macromolecular biosynthesis (see Fig. 7.22). In this case, Akt phosphorylates and inactivates the TSC complex, a GAP for the small GTPase Rheb. This leads to Rheb activation, and in turn, to the activation of mTOR. The mTOR pathway has multiple effects on cellular metabolism; collectively, these changes are essential to provide the raw materials needed to carry out the increased gene expression, protein production, and cell division that accompany T-cell activation. Specifically, mTOR activation leads to increased lipid production, ribosome biosynthesis, mRNA synthesis, and protein translation.
7-18 T-cell receptor signaling leads to enhanced integrin-mediated cell adhesion.
The third signaling module induced by TCR stimulation leads to enhanced integrin adhesion. Together with cytoskeletal changes (discussed in the next section), this process promotes stability of the T cell-APC interaction and localizes active signaling complexes into a structure known as the ‘immune synapse’ described below in Section 7-19 (and see Fig. 7.25). The immune synapse, the region of the T-cell membrane that is in direct and stable contact with the APC or target cell, is formed within minutes of T-cell receptor recognition of MHC/peptide ligands. One important component of this is increased adhesiveness of the T-cell integrin LFA-1. On nonstimulated T cells, LFA-1 resides in a low-affinity state and is well dispersed on the T-cell membrane, resulting in weak binding to its ligand, ICAM-1. Following T-cell receptor stimulation, LFA-1 molecules aggregate at the synapse, and also undergo a conformational change that converts each LFA-1 molecule into a high-affinity binding partner for ICAM-1. Together, these changes lead to enhanced adhesion between the T cell and the APC, and to stabilization of this cell–cell interaction. These effects on LFA-1 are induced by the recruitment of the adaptor protein ADAP to the LAT:Gads:SLP-76 scaffold complex (Fig. 7.23). In turn, ADAP recruits two additional proteins, SKAP55 and RIAM. The ADAP:SKAP55:RIAM complex binds to the small GTPase Rap1, activating Rap1 at the site of T-cell receptor signaling. GTP-bound Rap1 then promotes LFA-1 aggregation and the conformational change that converts LFA-1 into a high-affinity binding partner for ICAM-1. The importance of this pathway is underscored by the finding that ADAP-deficient T cells show impaired proliferation and cytokine production following T-cell receptor stimulation.
7-19 T-cell receptor signaling induces cytoskeletal reorganization by activating the small GTPase Cdc42.