Two-Compartment Model of NK Cell Proliferation: Insights from Population Response to IL-15 Stimulation

Abstract

NK cells are innate lymphocytes that mediate early host defense against viruses, such as cytomegalovirus. IL-15 is upregulated during viral infections and drives the expansion of NK cells. However, the influence of IL-15 on murine NK cell division and death rates has not been quantitatively studied. Therefore, we developed a series of two-compartment (representing quiescent and dividing NK cell subpopulations) mathematical models, incorporating different assumptions about the kinetic parameters regulating NK cell expansion. Using experimentally derived division and death rates, we tested each model’s assumptions by comparing predictions of NK cell numbers with independent experimental results and demonstrated that the kinetic parameters are distinct for nondividing and dividing NK cell subpopulations. IL-15 influenced NK cell expansion by modulating recruitment and division rates to a greater extent than death rates. The observed time delay to first division could be accounted for by differences in the kinetic parameters of nondividing and dividing subsets of NK cells. Although the duration of the time delay to first division was not significantly influenced by IL-15, the recruitment of nondividing NK cells into the replicating subpopulation increased with greater IL-15 concentrations. Our model quantitatively predicted changes in NK cell accumulation when IL-15 stimulation was reduced, demonstrating that NK cell divisional commitment was interrupted when cytokine stimulation was removed. In summary, this quantitative analysis reveals novel insights into the in vitro regulation of NK cell proliferation and provides a foundation for modeling in vivo NK cell responses to viral infections.