Abstract
Natural killer (NK) cells serve as one of the first lines of defense against viral infections and transformed cells. NK cell cytotoxicity is not dependent on antigen presentation by target cells, but is dependent on integration of activating and inhibitory signals triggered by receptor–ligand interactions formed at a tight intercellular contact between the NK and target cell, i.e., the immune synapse. We have studied the single-cell migration behavior and target-cell contact dynamics of resting and interleukin (IL)-2-activated human peripheral blood NK cells. Small populations of NK cells and target cells were confined in microwells and imaged by fluorescence microscopy for >8 h. Only the IL-2-activated population of NK cells showed efficient cytotoxicity against the human embryonic kidney 293T target cells. We found that although the average migration speeds were comparable, activated NK cells showed significantly more dynamic migration behavior, with more frequent transitions between periods of low and high motility. Resting NK cells formed fewer and weaker contacts with target cells, which manifested as shorter conjugation times and in many cases a complete lack of post-conjugation attachment to target cells. Activated NK cells were approximately twice as big as the resting cells, displayed a more migratory phenotype, and were more likely to employ “motile scanning” of the target-cell surface during conjugation. Taken together, our experiments quantify, at the single-cell level, how activation by IL-2 leads to altered NK cell cytotoxicity, migration behavior, and contact dynamics.
Highlights
Natural killer (NK) cells are large granular lymphocytes capable of clearing both virus-infected and transformed cells
The difference in average migration speed was small between resting and activated NK cells, a more detailed analysis revealed that resting NK cells were less likely than activated cells to transiently switch between different modes of migration
Overall, activated NK cells were more dynamic with a broader range of morphologies consistent with alterations between migration, stopping, and immune synapse formation
Summary
Natural killer (NK) cells are large granular lymphocytes capable of clearing both virus-infected and transformed cells. The immunostimulatory properties of IL-2 have been used in cancer treatment [8] where it has been shown to selectively lead to NK cell expansion when given in relatively low doses over extended periods of time [9]. It is poorly understood under what conditions NK cells can be stimulated by endogenous IL-2, even though cross-talk between NK cells and IL-2-producing T cells has been reported, linking the innate and adaptive immune systems [10,11,12]
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