The body’s immune cells can naturally fight off viral and bacterial microbes and other invaders, but they can also be “trained” to respond even more aggressively and powerfully to such threats, according to scientists at the University of California, Los Angeles, who discovered the fundamental rule underlying this process in a certain class of cells.
In a study published in the journal Science, researchers identified a key molecular mechanism within macrophages, the cells of the innate immune system that fight infections, that determines whether and how well these cells can be trained. Their findings could help pave the way for future targeted strategies to enhance immune system function.
“Like a soldier or an athlete, innate immune cells can be trained by past experience to better fight infections,” said lead author Quen Cheng, associate professor of infectious disease clinical professor at the David Geffen School of Medicine at the University of California, Los Angeles.
However, he noted that earlier researchers had observed that some immune training experiments appeared to be better than others. “This amazing discovery prompted us to better understand the rules governing this process.”
Whether immune training takes place depends on how the cell’s DNA is wrapped. In human cells, for example, more than 6 feet of DNA must fit into the cell nucleus, which is so small that it cannot be seen with the naked eye. To achieve this, DNA is tightly wrapped in chromosomes.
Only select stretches of DNA are open and accessible, and only genes in those accessible areas are able to respond and fight infection, said senior author Alexander Hoffmann, Thomas M. Asher professor of microbiology at the University of California Los Angeles and director of the Institute for Quantitative and Computational Computing. Biological Sciences.
However, by introducing a stimulus into a macrophage, for example, a substance derived from a microbe or pathogen, as in the case of a vaccine, the pre-compacted regions of DNA can be unfolded. This disclosure opens up new genes that will allow the cell to respond more aggressively, essentially training it to fight the next infection, Hoffmann said.
New research shows that the precise dynamics of a key immune signaling molecule in macrophages, called NFB, determines whether this gene unfolding and unfolding occurs. Moreover, the researchers report, the dynamic activity of NFB itself is determined by the exact type of extracellular stimulus introduced into the macrophage.
“It’s important to note that our research shows that innate immune cells can be trained to become more aggressive only with some stimuli and not others,” Cheng said. “This specificity is critical to human health because proper exercise is essential to effectively fight infection, but improper exercise can lead to too much inflammation and autoimmunity, which can cause significant damage.”
NFB helps immune cells identify incoming threats. When immune cell receptors detect threatening external stimuli, they activate the NFB molecule within the cell. The dynamics of the NFB – the way it behaves over time – forms a Morse-like language with which it communicates the external threat to DNA and tells it which genes should be ready for battle.
The exact “word” of this code that the NFB uses to tell the DNA to unfold depends on whether the NFB is oscillating or stable for eight or more hours after being hit with a stimulus. Fluctuating NFB accumulates in the nucleus of the macrophage, then moves into the cytoplasm, and then returns to the nucleus cyclically, like a pendulum. Not wobbling or stable, the NFB moves to the nucleus and stays there for several hours.
Using advanced microscopy, the researchers tracked NFB activity in macrophages obtained from the bone marrow of healthy mice, tracking how the dynamics of the molecule changes in response to several different stimuli. They found that NFB successfully trained macrophages – unwrapping DNA and exposing new infection-fighting genes – only when stimulus-induced non-oscillatory NFB activity.
“For a long time, we intuitively knew it was important whether the NFB fluctuated or not, but we just couldn’t figure out how to do it,” Cheng said. “These results are a real breakthrough in understanding the language of immune cells, and knowing the language will help us hack the system to improve immune function.”
The researchers were also able to model this training process with a mathematical model, Hoffmann said, and the predicted insights they gained could allow for the precision development of trained immunity in the future. Mathematical modeling of immune regulatory systems is a key goal of his laboratory, allowing the use of predictive modeling for precision medicine.
Cheng earned his PhD under Hoffmann’s UCLA Specialty Training and Advanced Research, or STAR, program for medical scientists.
Hoffmann and Cheng expect this study to inspire a wide range of additional research, including studies on human diseases caused by improperly trained immune cells, strategies to optimize immune training to fight infection, and ways to complement existing vaccine approaches.
“This study shows how collaboration between researchers at UCLA College and David Geffen School of Medicine can lead to the creation of innovative and effective scientific knowledge that will benefit human health,” Hoffmann said.