PKC-theta Selectively Controls the Adhesion-Stimulating Molecule Rap1

Blood. 2008 Dec 1;112(12):4617-27. doi: 10.1182/blood-2007-11-121111. Epub 2008 Sep 16.

Abstract

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. beta(2) 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- theta (PKC-theta)/RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T-cell activation, the direct phosphorylation of RapGEF2 at Ser960 by PKC- theta 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- theta. These data define that, among other pathways acting on LFA-1 regulation, PKC- theta and its effector RapGEF2 are critical factors in TCR signaling to Rap1. Taken together, PKC- theta sets the threshold for T-cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics*
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Isoenzymes / physiology*
  • Jurkat Cells
  • Lymphocyte Function-Associated Antigen-1 / physiology
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Protein Kinase C / physiology*
  • Protein Kinase C-theta
  • RNA, Small Interfering / pharmacology
  • Substrate Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology*
  • Up-Regulation / genetics
  • Up-Regulation / physiology
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • Guanine Nucleotide Exchange Factors
  • Isoenzymes
  • Lymphocyte Function-Associated Antigen-1
  • Nerve Tissue Proteins
  • RAPGEF2 protein, human
  • RNA, Small Interfering
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta
  • rap1 GTP-Binding Proteins