UCLA researchers have discovered the fundamental rule that allows the human body's immune cells to be trained to aggressively respond to viruses, bacteria and other invaders, the university announced Thursday.
UCLA researchers identified a molecular mechanism within macrophages, which are infection-fighting cells in the innate immune system, that determines whether and how well the cells can be trained to fight invaders.
“Like a soldier or an athlete, innate immune cells can be trained by past experiences to become better at fighting infections,” said the study's lead author, Quen Cheng, an assistant clinical professor of infectious diseases at UCLA's Geffen School of Medicine.
Cheng noted that some experiences appear to be better than others for immune training, and that “this surprising finding motivated us to better understand the rules that govern this process.”
The study was published in the journal “Science” Friday, according to UCLA, which added that the findings could lead to strategies that enhance the immune system's function.
Researchers found that immune training can occur if a cell's DNA becomes unwrapped and exposes new genes that enable the cell to respond more aggressively, according to the study's senior author Alexander Hoffman, professor of microbiology and director of the Institute for Quantitative and Computational Biosciences. When DNA is wrapped, only selected regions are exposed and accessible to fight an infection.
The UCLA researchers found that the precise dynamics of a key immune signaling molecule in macrophages, which is called NFKB and helps immune cells identify threats, determine if the DNA unwraps and genes are exposed.
Researchers also reported that the dynamic activity of NFKB itself is determined by the precise type of extracellular stimulus introduced to the macrophages.
“Importantly, our study shows that innate immune cells can be trained to become more aggressive only by some stimuli and not others,” Cheng said. “This specificity is critical to human health because proper training is important for effectively fighting infection, but improper training may result in too much inflammation and autoimmunity, which can cause significant damage.”
The NFKB is activated when receptors on the immune cells detect threatening external stimuli. The dynamics of NFKB form a language that UCLA researchers compared to Morse code -- it communicates to the DNA that there is an external threat and tells the genes to get ready for battle.
Researchers used the bone marrow of mice to follow the activity of NFKB in macrophages, according to UCLA. They tracked how the molecule's dynamics changed in response to several stimuli. NFKB was successful only when the stimulus induced non-oscillating NFKB activity.
“For a long time, we've known intuitively that whether NFKB oscillates or not must be important, but have simply not been able to figure out how,” Cheng said. “These results are a real breakthrough for understanding the language of immune cells, and knowing the language will help us `hack' the system to improve immune function.”
The training process was simulated with a mathematical model, as well, UCLA said. Mathematical modeling of immune regulatory systems is a key goal of Hoffman's laboratory.
Hoffman and Cheng expect to inspire a wide range of other studies from their research, including investigations into diseases caused by immune cells, strategies to improve immune training to fight infections and how to complement existing vaccine approaches.
“This study shows how collaborations between researchers in the UCLA College and David Geffen School of Medicine can produce innovative and impactful science that benefits human health,” Hoffmann said. Cheng earned his Ph.D. under Hoffman's guidance at UCLA's Specialty Training and Advanced Research program.
The study's co-lead author is Sho Ohta, an assistant professor at the University of Tokyo and a former postdoctoral scholar in Hoffmann's UCLA laboratory. Co-authors also include UCLA M.D. and Ph.D. student Katherine Sheu; Roberto Spreafico, a former postdoctoral scholar in Hoffmann's laboratory; Adewunmi Adelaja, UCLA M.D. student who earned his Ph.D. in Hoffmann's laboratory; and Brooks Taylor, a former UCLA doctoral student in Hoffmann's laboratory.
The study was funded by UCLA's Department of Medicine's STAR Program and the National Institutes of Health.