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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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IMMUNOBIOLOGY
PKC- selectively controls the adhesion-stimulating molecule Rap1
Thomas Letschka1,
Veronika Kollmann1,
Christa Pfeifhofer-Obermair1,
Christina Lutz-Nicoladoni1,
Gerald J. Obermair2,
Friedrich Fresser1,
Michael Leitges3,
Natascha Hermann-Kleiter1,
Sandra Kaminski1, and
Gottfried Baier1
1 Department for Medical Genetics, Molecular and Clinical Pharmacology and
2 Department for Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria; and
3 Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
The antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunologic synapse (IS) between the membranes of the 2 cells. β2 integrins on the T cell, namely, leukocyte function-associated antigen 1 (LFA-1) and its counter ligand, namely, immunoglobulin-like cell adhesion molecule 1 (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 (TCR) have not been resolved. In the present study, we identified a previously unknown function of a protein kinase C- (PKC-)/RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T-cell activation, the direct phosphorylation of RapGEF2 at Ser960 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 TCR 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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