The integrin LFA-1 is essential for efficient activation and for cytotoxicity of NK cells because it initiates the assembly of the immunological synapse and mediates firm adhesion to the target. LFA-1 is also needed to polarize the cytotoxic machinery of the NK cell toward the target cell. The binding affinity and avidity of integrins can be regulated via inside-out signals from other receptors. In this article, we investigate the signals necessary to activate LFA-1 in human NK cells. Our data show that LFA-1 has a low ligand-binding activity in resting human NK cells, but it can be stimulated by triggering activating receptors, such as 2B4 or CD16, or by coactivation of different receptor combinations. Short-term stimulation of freshly isolated NK cells with cytokines, such as IL-15, IL-12, or IL-18, does not activate LFA-1 but increases the responsiveness of the cells to subsequent receptor stimulation. Different NK cell subsets vary in their ability to induce LFA-1 binding activity after activating receptor stimulation. Interestingly, the NK cell subsets that are more mature and possess higher cytotoxic potential also show the highest activation of LFA-1, which correlated with the expression of the small calcium-binding protein S100A4. Our data suggest that regulation of LFA-1 is one reason for the different activity of NK cells during differentiation.
This article is featured in In This Issue, p.1763
This work was supported by the Leibniz Association (SAW-2013-IfADo-2) and the Deutsche Forschungsgemeinschaft (WA-1552/5-1).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Ab-dependent cellular cytotoxicity
- killer cell Ig-like receptor
- ligand complex–based adhesion assay
- mean fluorescence intensity
- room temperature
- Received June 9, 2016.
- Accepted December 27, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.