The study reveals how immune cells can be trained to fight infections


In this image from a microscopy video, scientists monitor NFκB activity inside the cell as it responds to a stimulus. Credit: Brooks Taylor / UCLA

The body’s immune cells naturally fight viral and bacterial microbes and other invaders, but they can also be reprogrammed or “trained” to respond more aggressively and powerfully to these threats, according to UCLA scientists who have discovered the rule. fundamental underlying in this process particular class of cells.

In a study published June 18 in the journal Science, the researchers identified a key molecular mechanism within macrophages, fighting infections of the innate immune system, which determines whether cells can train and how well. Their findings could help pave the way for future strategies aimed at improving the function of the immune system.

“As a soldier or an athlete, innate immune cells can be formed from past experiences to improve the fight against infections,” said lead author Quen Cheng, an assistant professor of infectious disease at the David Geffen School of Infectious Diseases. UCLA Medicine. However, he noted, researchers had previously noted that some experiences appeared to be better than others for immunity. . “This startling finding motivated us to better understand the rules that govern this process.”

Whether immune training occurs depends on how the cell’s DNA is wrapped. In , for example, more than 6 feet of DNA must fit into the nucleus of the cell, which is so small that it is not visible to the naked eye. To achieve this feat, DNA is well wrapped in chromosomes.

Only selected regions of DNA are exposed and accessible, and only genes in those accessible regions are able to respond and , said lead author Alexander Hoffmann, Thomas M. Asher, professor of microbiology at UCLA and director of the Institute of Quantitative and Computational Biosciences.

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 — previously compacted regions of DNA can be unwrapped. This development exposes new genes that will allow the cell to respond more aggressively, essentially training it to fight the next infection, Hoffmann said.

New research reveals that the precise dynamics of a key molecule of immune signaling in macrophages, called NFκB, determines whether or not this gene development and exposure occurs. In addition, according to the researchers, the dynamic activity of NFκB itself is determined by the precise type of extracellular stimulus introduced into the macrophage.

“It’s important to note that our study shows that innate immune cells can be trained to be more aggressive only by some stimuli and not by others,” Cheng said. “This specificity is critical to human health, as proper training is important to effectively fight infection, but inadequate training can lead to excessive inflammation and autoimmunity, which can cause significant damage.”

NFκB helps immune cells identify incoming threats. When receptors on immune cells detect threatening external stimuli, they activate the NFκB molecule inside the cell. The dynamics of NFκB — as it behaves over time — form a language similar to Morse code by which it communicates the identity of the external threat to DNA and tells it which genes will need to be prepared for battle.

The specific “word” in this code that NFκB uses to tell the DNA to unfold depends on whether NFκB is oscillating or stable for eight or more hours after finding a stimulus. Oscillating NFκB accumulates in the nucleus of a macrophage, moves into the cytoplasm, and returns to the nucleus in cycles, like an oscillating pendulum. NFκB, not oscillating or constant, moves to the core and stays there for several hours.

Using advanced microscopy, the researchers tracked NFκB activity in macrophages derived from the bone marrow of healthy mice, tracking how the molecule dynamics changed in response to several different stimuli. They found that NFκB was successful in training macrophages — unwrapping DNA and exposing new genes that fought infections — only when the stimulus induced non-oscillating NFκB activity.

“For a long time, we knew intuitively that whether NFκB oscillates or not should be important, but we just couldn’t figure out how,” 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 simulate this training process with a , and the predictive understanding they picked up may allow for future engineering aimed at the accuracy of trained immunity, Hoffmann said. Mathematical modeling of immune regulation systems is a key goal of his laboratory in order to use predictive simulations for precision medicine.

Cheng earned his doctorate. under Hoffmann’s guidance through UCLA’s specialized training and advanced research program, or STAR, for scientific physicians.

Hoffmann and Cheng hope that this research will inspire a wide range of additional studies, including research on human diseases caused by that have not been incorrectly trained, strategies to optimize immune training to fight infection, and ways to complement existing vaccine approaches.

“This study shows how collaborations between researchers at UCLA College and the David Geffen School of Medicine can produce an innovative and impactful science that benefits human health,” Hoffmann said.

Scientists decode the “language” of immune cells

More information:
Quen J. Cheng et al, NF-κB dynamics determine the specificity of the epigenomic reprogramming stimulus in macrophages, Science (2021). DOI: 10.1126 / science.abc0269

Citation: Study Reveals How Immune Cells Can Be Trained to Fight Infections (2021, June 24) Retrieved June 24, 2021 at -cells-infections.html

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