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          Institute: MPI für molekulare Biomedizin     Collection: Yearbook 2013     Display Documents

ID: 648345.0, MPI für molekulare Biomedizin / Yearbook 2013
CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules
Authors:Kliche, S.; Worbs, T.; Wang, X.; Degen, J.; Patzak, I.; Meineke, B.; Togni, M.; Moser, M.; Reinhold, A.; Kiefer, F.; Freund, C.; Forster, R.; Schraven, B.
Date of Publication (YYYY-MM-DD):2012-01-19
Title of Journal:Blood
Issue / Number:3
Start Page:777
End Page:785
Review Status:Internal review
Audience:Not Specified
Abstract / Description:The beta2-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 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 probably because of 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 2 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, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7
Free Keywords:A; analysis; Antigen-Presenting Cells; Endothelium; immunology
External Publication Status:published
Document Type:Article
Communicated by:keuker
Affiliations:MPI für molekulare Biomedizin
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