Bystander cells enhance NK cytotoxic efficiency by reducing search time

Abstract

Natural killer (NK) cells play a central role during innate immune responses by eliminating pathogen-infected or tumorigenic cells. In the microenvironment, NK cells encounter not only target cells but also other cell types including non-target bystander cells. The impact of bystander cells on NK killing efficiency is, however, still elusive. In this study we show that the presence of bystander cells, such as P815, monocytes or HUVEC, enhances NK killing efficiency. With bystander cells present, the velocity and persistence of NK cells were increased, whereas the degranulation of lytic granules remained unchanged. Bystander cell-derived H2O2 was found to mediate the acceleration of NK cell migration. Using mathematical diffusion models, we confirm that local acceleration of NK cells in the vicinity of bystander cells reduces their search time to locate target cells. In addition, we found that integrin β chains (β1, β2 and β7) on NK cells are required for bystander-enhanced NK migration persistence. In conclusion, we show that acceleration of NK cell migration in the vicinity of H2O2-producing bystander cells reduces target cell search time and enhances NK killing efficiency.

Acquisition of cell migration defines NK cell differentiation from hematopoietic stem cell precursors

“…On average, observed progenitor cell speeds at all stages were similar to those measured for immortalized NK cell lines as well as those seen in other studies looking at lymphocyte motility, both in vitro ( Khorshidi et al. , 2011 ; Zhou et al. , 2017 ) and in vivo ( Miller et al.…”

“…Additionally, the increased heterogeneity in cell migration at later stages may correspond to NK cells with different functional capabilities, with cells exhibiting greater motility being more effective at cell-mediated cytotoxicity ( Choi and Mitchison, 2013 ; Forslund et al. , 2015 ; Zhou et al. , 2017 ).…”

On the efficiency of chemotactic pursuit - Comparing blind search with temporal and spatial gradient sensing

“…The present work was motivated by experiments on chemotactic ‘pursuit’ in a Petri dish. These experiments studied the interaction of natural killer (NK) cells 43 with 293T embryonic kidney cells 2 or K562 leukemic cells 3 as targets. These in-vitro experiments demonstrated that single immune cells are able to find their targets on their own account.…”

“…Although this work is not focused on particular types of immune and target cells, we are using size and migration parameters for the simulated cells that are roughly compatible with existing experiments, in particular those involving natural killer cells and K562 leukemia cells 3 .…”

“…This recruitment of immune cells is often based on endogenous chemo-attractants, which are released by other host cells that are already at the location where a pathogen has invaded the body. However, the fact that individual immune cells are able to find and eliminate tumor cells in a Petri dish 2,3 , without any assistance, suggests that immune cells can detect chemical traces emitted by the pathogens themselves. We therefore investigate in this work how efficient a self-propelled agent (such as an immune cell) can hypothetically become in finding and elliminating randomly distributed, mobile targets (such as tumor cells), a problem that is related to the more general topics of pursuit and evasion 4 , to foraging theory 5,6 , to the behavioral ecology of finding resources 7 , and even to robotic control theory 8 .…”