Medical Professional Publications

Mathematical Model Shines Light on Immune Cell Communication

(From the August 2017 issue of Research Now)

Natural killer (NK) cells are a key part of the innate immune system, activating to destroy virally infected cells or tumor cells detected in the body. While researchers know how NK cells identify foreign cells, some aspects of NK cellular communication are still unknown. Because of the large number of molecules and proteins interacting with NK cells, which are unique to each individual, it is nearly impossible to determine how NK cells activate simply by looking at samples.

A recent study published in Science Signaling investigated the relationship between two components of the immune response. By constructing a mathematical computer model and using blood samples to determine its accuracy, the research team found out how NK cells can be activated and how the two immune components – a signaling molecule called IL-2 and a receptor on the surface of NK cells called NKG2D – do not physically interact but communicate through signaling inside the NK cell.

“The immune system is so complex that we cannot gain insight into how it works without modeling,” says Jayajit Das, PhD, a faculty member of the Battelle Center for Mathematical Medicinein The Research Institute at Nationwide Children’s Hospital and senior author of the study. “By using the model, we can run trials to try out different ways we think IL-2 signaling molecules and NKG2D surface receptors communicate. Then, based on our available data, we can give an accurate model of this communication and mechanistically understand it.”

Dr. Das created the mathematical model of NK cells as part of the larger research effort conducted at Dr. Lewis Lanier’s laboratory at the University of California, San Francisco. With the assistance of a technique developed at Stanford University, it is now possible to analyze up to 40 proteins at once and observe NK cell interactions at the cell-to-cell level. This gave Dr. Das enough information to build a mathematical model to characterize part of a process as complex as NK cell signaling and activation. It was determined that IL-2 allowed NKG2D to stimulate a strong NK cell activation to destroy infected target cells, despite no direct contact of the signaling molecule, IL-2 and the surface receptor, NKG2D. Essentially, IL-2 indirectly turned the beginning of the immune response ‘on’.

“The synergy between these two pathways is clinically important and could eventually lead to medications that help activate natural killer cells to destroy targets such as cancer or infectious diseases,” adds Dr. Das. “But in order to do that, we needed to mechanistically understand that synergy, which was only possible by combining large data sets and advanced computational analysis.”

Mukherjee, S, Jensen H, Stewart W, Stewart D, Ray W, Chen S, Nolan G, Lanier L, Das J. In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells. Science Signaling. 27 Jun 2017

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