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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4617-4627.
Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2007-11-121111.
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Submitted November 5, 2007
Accepted July 10, 2008
PKC selectively controls the adhesion-stimulating molecule Rap1
Thomas Letschka, Veronika Kollmann, Christa Pfeifhofer-Obermair, Christina Lutz-Nicoladoni, Gerald J Obermair, Friedrich Fresser, Michael Leitges, Natascha Hermann-Kleiter, Sandra Kaminski, and Gottfried Baier*
Department for Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
Department for Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria
The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
* Corresponding author; email: gottfried.baier{at}i-med.ac.at.
The antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunological synapse (IS) between the membranes of the two cells.  2-integrins on the T cell, namely LFA-1 and its counter ligand, namely ICAM-1 on the APC, critically stabilize this intercellular interaction. The small GTPase Rap1 controls T cell adhesion through modulating the affinity and/or spatial organization of LFA-1; however, the upstream regulatory components triggered by the T cell receptor have not been resolved. In the present study, we identified a previously unknown function of a PKC : RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T cell activation, the direct phosphorylation of RapGEF2 at Ser-960 by PKC regulates Rap1 activation as well as LFA-1 adhesiveness to ICAM-1. In OT-II TCR-transgenic CD4+ T cells, clustering of LFA-1 after antigen-activation was impaired in the absence of PKC. These data define that, among other pathways acting on LFA-1 regulation, PKC and its effector RapGEF2 are critical factors in T cell receptor signaling to Rap1. Taken together, PKC sets the threshold for T cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.
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