The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells (APCs) and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55-module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T cell motility in vivo. This is likely due to a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55-module regulates CCR7-induced integrin activation revealed that two independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, two independent ADAP/SKAP55-modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.
- Submitted June 20, 2011.
- Accepted November 6, 2011.
- Copyright © 2005 American Society of Hematology