Research ResourceImmunology

In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells

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Sci. Signal.  27 Jun 2017:
Vol. 10, Issue 485, eaai9062
DOI: 10.1126/scisignal.aai9062

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Searching for synergy

Natural killer (NK) cells detect and kill virally infected and transformed cells. NK cell activation depends on the balance between signaling by inhibitory and activating receptors, and cytokine signaling can synergize with activating receptor signaling to induce NK cell activation. Mukherjee et al. performed mass cytometry analysis of the abundances of more than 30 proteins and computational analysis of the relationships between those changes in abundance. The authors delineated the mechanism underlying the synergy between signaling by the cytokine interleukin-2 (IL-2) and subsequent stimulation of the activating receptor NKG2D in immature and mature subsets of human NK cells. This analysis predicted and experiments verified that the IL-2–stimulated increase in the abundance of the phosphatase CD45 in immature NK cells was the major determinant of the enhanced responses of these cells to NKG2D stimulation. The application of this type of analysis to other immune cell types will help to discover other synergies underlying cellular activation and function.

Abstract

Natural killer (NK) cells perform immunosurveillance of virally infected and transformed cells, and their activation depends on the balance between signaling by inhibitory and activating receptors. Cytokine receptor signaling can synergize with activating receptor signaling to induce NK cell activation. We investigated the interplay between the signaling pathways stimulated by the cytokine interleukin-2 (IL-2) and the activating receptor NKG2D in immature (CD56bright) and mature (CD56dim) subsets of human primary NK cells using mass cytometry experiments and in silico modeling. Our analysis revealed that IL-2 changed the abundances of several key proteins, including NKG2D and the phosphatase CD45. Furthermore, we found differences in correlations between protein abundances, which were associated with the maturation state of the NK cells. The mass cytometry measurements also revealed that the signaling kinetics of key protein abundances induced by NKG2D stimulation depended on the maturation state and the pretreatment condition of the NK cells. Our in silico model, which described the multidimensional data with coupled first-order reactions, predicted that the increase in CD45 abundance was a major enhancer of NKG2D-mediated activation in IL-2–treated CD56bright NK cells but not in IL-2–treated CD56dim NK cells. This dependence on CD45 was verified by measurement of CD107a mobilization to the NK cell surface (a marker of activation). Our mathematical framework can be used to glean mechanisms underlying synergistic signaling pathways in other activated immune cells.

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