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Inhibitory Receptor Crosslinking Quantitatively Dampens Calcium Flux Induced by Activating Receptor Triggering in NK

Sridharan Ganesan1, Petter Höglund1,2

  • 1Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden.

Frontiers in Immunology
|January 30, 2019
PubMed

Insights

Natural killer (NK) cell function relies on a balance of activating and inhibitory receptors. This study reveals how these receptors quantitatively regulate calcium (Ca2+) signaling in NK cells.

Area of Science:

  • Immunology
  • Cellular signaling
  • NK cell biology

Background:

  • Natural killer (NK) cell activity is governed by a complex interplay between activating and inhibitory receptors.
  • The precise mechanisms regulating this balance and its impact on cellular signaling remain incompletely understood.

Purpose of the Study:

  • To investigate the quantitative regulation of calcium (Ca2+) flux in NK cells by the interplay of activating and inhibitory receptors.
  • To explore how specific receptor interactions, such as H2D d and Ly49A, influence NK cell signaling.
  • To examine the effect of interleukin-15 (IL-15) priming on NK cell receptor-mediated signaling.

Main Methods:

  • Development of a flow cytometry-based assay to measure Ca2+ flux.
  • Antibody-mediated triggering of activating receptors with or without co-crosslinking of inhibitory receptors.
  • Analysis of both murine and human NK cells.

Main Results:

  • Inhibitory receptor co-crosslinking quantitatively regulates activating receptor-induced Ca2+ flux in both murine and human NK cells.
  • Activating and inhibitory receptor signaling operate in an additive manner, highlighting a finely tuned balance.
  • Murine NK cell expression of H2D d was found to reduce the inhibitory capacity of Ly49A, suggesting a cis-interaction.
  • IL-15 priming enhances Ca2+ flux upon activating receptor signaling without compromising inhibitory receptor function.

Conclusions:

  • NK cell inhibition is quantitatively regulated by the balance of activating and inhibitory receptors, impacting proximal signaling.
  • Specific receptor interactions, like cis-interactions between H2D d and Ly49A, can modulate inhibitory signal strength.
  • IL-15 priming potentiates NK cell responses while maintaining the integrity of inhibitory pathways.
Keywords:
IL-15Ly49MHC class INK cellsNKG2Acalcium fluxinhibitionquantitative

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