How immune cells signal complex information through the cellular network

The immune system is a complex network of signals among cells that can quickly relay information about the location and severity of foreign invaders.

But just how far these signals travel, and what receiving cells can decode from them, has remained a mystery—one that researchers in the Pritzker School of Molecular Engineering (PME) at the University of Chicago wanted to solve.

Using simulations and cell culture experiments conducted on a microfluidic device, researchers within the lab of Prof. Savas Tay found that when pathogen signals propagate among cell populations, nearby cells secrete signaling molecules in waves, giving other cells information about the dose, duration, and distance to the pathogen. The distance the signals travel depends on the initial dose.

The results, published in Science Advances, could lead to a better understanding of our immune system and ultimately lead to more effective therapies to treat disease.

“We can now better understand how cells tune their signals to control transmission distance within immune networks, and how other cells can receive and interpret these signals in space and time,” Tay said.

Signals depend on dose

When pathogens invade a tissue, immune cells called macrophages coordinate gene expression in nearby cells by secreting proteins called cytokines. These cytokine signals relay information about the type of pathogen, its severity, and its location by activating transcription factors in cells (in this case, the transcription factors are a known pathway called NF-kB). These transcription factors shuttle into a cell’s nucleus and lead to expression of signal-specific response genes.

But researchers hadn’t yet studied just how these cytokine signals control this NF-kB signaling in space and time. In Tays’ lab, postdoctoral researcher Minjun Son and his collaborators developed a high-throughput microfluidic system that mimics conditions during infection. In the system, they could load specific immune cells within chambers, stimulate them with bacterial signals, and follow how the communication among cells unfolds.

By placing bacterial signals in the system and watching how live immune cells responded, they found that the signaling range varied according to the dose. When macrophages responded by sending out a quick, large burst of cytokines, the signals traveled farther. When the cytokine release was slow, the signals did not travel as far. The researchers could see the network unfolding by tagging the transcription factor with fluorescent proteins and watching the cells light up in waves as the signals moved through.

A better understanding of the immune system

When the researchers analyzed the response at the single cell level, they found that cytokine dose and distance from the source could be quantified independently, showing that cells that receive these signals can decode information about dose, duration, and distance to the signal-secreting cells (macrophages).

“This shows that receiving cells can interpret complex environmental information to coordinate their response in spatial context,” Son said. “Now we can more deeply understand how different cells communicate over distance within the tissue in our body.”

Son says they hope to extend their microfluidic system to create an even more complex system that better mimics the body. A better understanding of the complex signaling within the immune system could help scientists and engineers more fully understand how the body responds to viruses and bacteria, which in turn could ultimately lead to better understanding of immunity and autoimmunity, and the creation of better therapies.

Other authors on the paper include Tino Frank, Thomas Holst-Hansen, Andrew Wang, Michael Junkin, Sara S. Kashaf, and Ala Trusina.

Citation: “Spatiotemporal NF-κB dynamics encodes the position, amplitude and duration of local immune inputs,” Son et al, Science Advances, August 31, 2022. DOI: 10.1126/sciadv.abn6240

Funding: National Institutes of Health, Army Research Office, Danish National Research Foundation