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PKC-theta selectively controls the adhesion-stimulating molecule Rap1.

Thomas Letschka1, Veronika Kollmann, Christa Pfeifhofer-Obermair

  • 1Department for Medical Genetics, Innsbruck Medical University, Innsbruck, Austria.

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Summary

Protein kinase C-theta (PKC-theta) and RapGEF2 regulate T-cell adhesion by controlling leukocyte function-associated antigen 1 (LFA-1) avidity. This PKC-theta/RapGEF2 complex is crucial for T-cell receptor signaling, impacting T-cell activation and immune responses.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • T cell-APC interaction forms an immunologic synapse (IS), stabilized by LFA-1 on T cells and ICAM-1 on APCs.
  • The small GTPase Rap1 modulates LFA-1 affinity and spatial organization, controlling T cell adhesion.
  • Upstream regulators of Rap1 activation by the T cell receptor (TCR) remain incompletely understood.

Purpose of the Study:

  • To identify novel upstream regulatory components involved in TCR-mediated LFA-1 avidity regulation.
  • To elucidate the role of a protein kinase C-theta (PKC-theta)/RapGEF2 complex in T lymphocyte adhesion.

Main Methods:

  • Investigated the function of the PKC-theta/RapGEF2 complex in LFA-1 avidity regulation.
  • Analyzed the effect of PKC-theta phosphorylation of RapGEF2 on Rap1 activation and LFA-1 adhesiveness.
  • Examined LFA-1 clustering in T cells lacking PKC-theta after antigen activation.

Main Results:

  • Identified a novel function for the PKC-theta/RapGEF2 complex in regulating LFA-1 avidity in T lymphocytes.
  • Demonstrated that PKC-theta directly phosphorylates RapGEF2 at Ser960, which regulates Rap1 activation and LFA-1 adhesiveness to ICAM-1.
  • Observed impaired LFA-1 clustering in OT-II TCR-transgenic CD4+ T cells deficient in PKC-theta following antigen activation.

Conclusions:

  • PKC-theta and its effector RapGEF2 are critical mediators in TCR signaling to Rap1, influencing LFA-1 regulation.
  • PKC-theta positively regulates both cytokine responses and T lymphocyte adhesive capacities, thereby setting the threshold for T cell activation.