Mechanistic Model of Natural Killer Cell Proliferative Response to IL-15 Receptor Stimulation

Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation.Author Summary: Natural killer (NK) cells are innate immune cells that are important in our bodies' initial defenses against pathogens, like viruses. NK cells rapidly proliferate early during viral infections to provide an expanded pool of effector cells to suppress the infection. This proliferative response is driven by a cytokine called interleukin-15 (IL-15); however, the influence of IL-15 and its receptor (IL-15R) in stimulating NK cell proliferation has not been quantitatively characterized at the cellular level. To better understand the factors controlling the vigorous expansion of NK cells during infections, we developed a mathematical model incorporating IL-15R binding and trafficking parameters that regulate the number of cell-surface IL-15/IL-15R signaling complexes. The analysis of this model provided us with insight on how IL-15-driven NK cell expansion can be modulated through changes in receptor kinetics and expression. Based on model predictions, we were able to draw inferences about NK cell population dynamics and to compare these conclusions with quantitative experimental results. Our results and model have applicability to studies designed to manipulate cell responses in the context of immunotherapies.