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The adaptor protein Crk controls activation and inhibition of natural killer cells

Dongfang Liu1, Mary E Peterson, Eric O Long

  • 1Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.

Immunity
|April 3, 2012
PubMed

Insights

Natural killer (NK) cell inhibitory receptors use Crk phosphorylation to block activation signals. This mechanism maintains NK cell responsiveness by preventing F-actin buildup at inhibitory synapses.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Natural killer (NK) cell inhibitory receptors prevent NK cell activation by recruiting tyrosine phosphatases.
  • The adaptor protein Crk plays a role in NK cell activation, but its function in inhibition is unclear.

Purpose of the Study:

  • To investigate the role of the adaptor protein Crk in NK cell inhibition mediated by the CD94-NKG2A receptor.
  • To elucidate the molecular mechanisms by which inhibitory receptors regulate NK cell synapses.

Main Methods:

  • Primary NK cells were imaged using lipid bilayers containing activating (Fc) and inhibitory (HLA-E) ligands.
  • Crk phosphorylation and its role in microcluster movement, F-actin buildup, and signaling were analyzed.

Main Results:

  • HLA-E induced Crk phosphorylation in NKG2A(+) NK cells.
  • Crk was essential for Fc microcluster movement and activation signaling at activating synapses.
  • At inhibitory synapses, HLA-E promoted central accumulation of Fc and phosphorylated Crk, and blocked F-actin buildup.

Conclusions:

  • Crk phosphorylation is a key event in NK cell inhibition, preventing essential Crk-dependent activation signals.
  • Inhibitory receptor function involves blocking F-actin network formation, which may reduce constraints on subsequent activation receptor engagement.

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