Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally

Abstract

NK cell activation is regulated by a balance between activating and inhibitory signals. To address the question of how these signals are spatially integrated, we created a computer simulation of activating and inhibitory NK cell immunological synapse (NKIS) assembly, implementing either a “quantity-based” inhibition model or a “distance-based” inhibition model. The simulations mimicked the observed molecule distributions in inhibitory and activating NKIS and yielded several new insights. First, the total signal is highly influenced by activating complex dissociation rates but not by adhesion and inhibitory complex dissociation rates. Second, concerted motion of receptors in clusters significantly accelerates NKIS maturation. Third, when the potential of a cis interaction between Ly49 receptors and MHC class I on murine NK cells was added to the model, the integrated signal as a function of receptor and ligand numbers was only slightly increased, at least up to the level of 50% cis-bound Ly49 receptors reached in the model. Fourth, and perhaps most importantly, the integrated signal behavior obtained when using the distance-based inhibition signal model was closer to the experimentally observed behavior, with an inhibition radius of the order 3–10 molecules. Microscopy to visualize Vav activation in NK cells on micropatterned surfaces of activating and inhibitory strips revealed that Vav is only locally activated where activating receptors are ligated within a single NK cell contact. Taken together, these data are consistent with a model in which inhibitory receptors act locally; that is, that every bound inhibitory receptor acts on activating receptors within a certain radius around it.

Human NK Cells Differ More in Their KIR2DL1-Dependent Thresholds for HLA-Cw6-Mediated Inhibition than in Their Maximal Killing Capacity

“…This assumption is based on the findings that cells with lower level of inhibitory receptors require more inhibitory ligands to achieve the same level of inhibition [9], [10], [12], as the probability of an inhibitory receptor finding its ligand depends on the number of ligands on the target cell (and vice-versa) [11]. We used a sigmoid threshold function (Equation 1), where S denotes the threshold of the NK cell clone in the same experiment, in units of (molecule numbers) 2 as it is given in terms of the MHC*KIR product.…”

“…It has been qualitatively shown that murine NK cells with a low level of inhibitory receptors require a higher level of inhibitory ligands to achieve an inhibition of lysis similar to that of cells expressing a high level of receptors [9], [10]. The reason for this may be that the probability of an inhibitory receptor finding its ligand depends on the number of ligands on the target cell (and vice-versa), as shown in our recent study of the dynamics of the NK cell immunological synapse [11]. Similarly, murine NK cells expressing low amounts of Ly49 inhibitory receptors required higher amounts of purified MHC class I protein to inhibit IFN-γ production, than cells expressing high amounts of inhibitory receptors [12].…”

Understanding natural killer cell regulation by mathematical approaches

“…One can also create hybrid models where different levels of description are modeled using different model types (Shahaf et al, 2008). Many such models of lymphocyte migration or molecular processed were published (e.g., Beltman et al, 2011; Kaplan et al, 2011). A review of ODE, DDE, PDE, stochastic, and ABM models in immunology, including a comparison of their relative advantages and disadvantages, has recently been published (Kim et al, 2009).…”

“…The simulation by Kaplan et al (2011) further showed that the concerted motion of receptors in clusters – such as those formed by molecule aggregation on certain membrane microdomains – significantly accelerates the maturation of the NK cell immunological synapse. Membrane microdomains have also been implicated by the study of Mesecke et al The mathematical modeling showed that the association of Src-family kinases with activating but not with inhibitory receptors was essential for the experimentally observed Vav activation (Mesecke et al, 2011).…”

“…An agent-based modeling study by Kaplan et al (2011) addressed the question how signals from activating and inhibitory receptors are spatially integrated within the NK cell immunological synapse. The study constructed a computer simulation of the assembly of the NK cell-target cell synapse, which was based on many experimental findings.…”