Mechanical Regulation of the Cytotoxic Activity of Natural Killer Cells

Mechanosensing has been recently explored for T cells and B cells and is believed to be part of their activation mechanism. Here, we explore the mechanosensing of the third type of lymphocytes - Natural Killer (NK) cells, by showing that they modulate their immune activity in response to changes in the stiffness of a stimulating surface. Interestingly, we found that this immune response is bell-shaped, and peaks for a stiffness of a few hundreds of kPa. This bell-shape behavior was observed only for surfaces functionalized with the activating ligand MHC class I polypeptide-related sequence A (MICA), but not for control surfaces lacking immunoactive functionalities. We found that stiffness does not affect uniformly all cells but increases the size of a little group of extra-active cells, which in turn contribute to the overall activation effect of the entire cell population. We further imaged the clustering of costimulatory adapter protein DAP10 on NK cell membrane and found that it shows the same bell -shape dependence to surface stiffness. Based on these findings, we propose a catch-bond-based model for the mechanoregulation of NK cell cytotoxic activity, through interaction of NKG2D activating receptors with MICA. Our findings reveal what seems to be "the tip of iceberg" of mechanosensation of NK cells, and provides an important insight on the mechanism of their immune signaling. Statement of SignificanceThe mechanical sensing of immune lymphocytes was recently demonstrated for T cells and B cells, but not for the third type of lymphocytes - Natural Killer (NK) cells. Interestingly, previous reports on lymphocyte mechanosensing were controversial, and showed either positive or negative changes in their immune activity with environmental stiffness, depending on the stiffness range. In this paper, we directly demonstrated that NK cells modulate their response with the stiffness of the stimulating surface, and this modulation has a bell-shape trend. We found that there is a strong correlation between the response to stiffness and clustering of adaptor proteins. Upon this correlation, we proposed a mechanosensing model based on the catch-bond nature of activating ligand-receptor complexes in NK cells.