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NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development

Vedrana Jelenčić1, Marko Šestan1, Inga Kavazović1

  • 1Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

Nature Immunology
|September 19, 2018
PubMed

Insights

Natural killer (NK) cell activation relies on receptor signals. This study reveals NKG2D, an activating receptor, sets the threshold for NCR1, another activating receptor, impacting tumor and infection control.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • Natural killer (NK) cell activation is regulated by a balance of signals from inhibitory and activating receptors.
  • The developmental setting of NK cell activation thresholds is primarily attributed to inhibitory receptor engagement.

Purpose of the Study:

  • To investigate the role of the activating receptor NKG2D in setting the activation threshold for the activating receptor NCR1.
  • To elucidate the molecular mechanisms underlying NKG2D's influence on NK cell reactivity.

Main Methods:

  • Utilized NKG2D-deficient (Klrk1-/-) mice and wild-type controls.
  • Analyzed NK cell activation, cytokine production (IFN-γ), and signal transduction pathways.
  • Investigated the involvement of adaptor proteins DAP12 and CD3ζ.

Main Results:

  • NKG2D deficiency (Klrk1-/-) enhanced control of tumors and cytomegalovirus infection.
  • This enhanced control was linked to improved NCR1-induced IFN-γ production.
  • NKG2D signaling during development influenced CD3ζ expression, impacting NCR1 signal transduction and NK cell responsiveness.

Conclusions:

  • An activating receptor (NKG2D) developmentally regulates the activity of another activating receptor (NCR1) on NK cells.
  • This interaction determines NK cell reactivity to cellular threats like tumors and infections.
  • Findings challenge the paradigm that only inhibitory receptors set NK cell activation thresholds.

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