Format

Send to

Choose Destination
Sci Signal. 2017 Jun 27;10(485). pii: eaai9062. doi: 10.1126/scisignal.aai9062.

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

Author information

1
Battelle Center for Mathematical Medicine, Research Institute at the Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
2
Department of Microbiology and Immunology and Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Statistics, The Ohio State University, Columbus, OH 43210, USA.
4
Department of Mathematics, University of Iowa, Iowa City, IA 52242, USA.
5
Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
6
Biophysics Program, The Ohio State University, Columbus, OH 43210, USA.
7
Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
8
Department of Microbiology and Immunology and Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA. lewis.lanier@ucsf.edu das.70@osu.edu.
9
Battelle Center for Mathematical Medicine, Research Institute at the Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA. lewis.lanier@ucsf.edu das.70@osu.edu.
10
Department of Physics, The Ohio State University, Columbus, OH 43210, USA.

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.

PMID:
28655861
PMCID:
PMC5556952
DOI:
10.1126/scisignal.aai9062
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center