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CCR7-mediated LFA-1 functions in T cells are regulated by two independent ADAP/SKAP55-modules

Stefanie Kliche, Tim Worbs, Xiaoqian Wang, Janine Degen, Irene Patzak, Bernhard Meineke, Mauro Togni, Markus Moser, Annegret Reinhold, Friedemann Kiefer, Christian Freund, Reinhold Förster and Burkhart Schraven

Abstract

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.