Antibodies, which recognize viruses and proteins that the body has encountered before, have long gotten most of the credit for giving the human immune system a memory.
Now, researchers at the University of Chicago Pritzker School of Molecular Engineering (UChicago PME) have discovered a new form of immune memory. Macrophages, a type of white blood cell, adjust their molecular signaling patterns immediately after an infection, the researchers found. This short-term memory changes how macrophages respond to subsequent infections and immune signals – sometimes giving the cells a type of tolerance that makes them less responsive, sometimes strengthening their immune response.
The new findings, published in Cell Systems, could eventually point toward new ways of controlling macrophage activity to treat infections or autoimmune diseases.
“It turns out that macrophages can turn up or down their responses based on what they’ve been exposed to,” said UChicago PME Prof. Savas Tay, senior author of the new work. “The better we understand how inflammatory signals are influencing cell states in this way, the better we can design new cell therapies that take advantage of these dials to control the immune system.”
Redefining immune memory
The human immune system has two lines of defense: the innate immune system acts quickly and non-specifically to detect and fight infections; the slower adaptive immune response recognizes and targets specific pathogens.
“Classically, what distinguishes the innate immune response from the adaptive immune response is that it doesn’t adapt; it doesn’t have a memory of prior stimuli,” said Andrew Wang, a University of Chicago MD/PhD student and first author of the new paper.
However, some recent studies have hinted that macrophages – part of the innate immune system – might vary their responses. Wang, Tay, and their colleagues wanted to investigate whether macrophages did indeed change over time.
To study this, they tested the impact of 80 different conditions – varying doses of six different bacterial and viral molecules – on macrophage activity using a high-throughput microfluidics platform they had previously designed. The exposure to inflammatory signals, they showed, sometimes led to a “priming” effect, making macrophages more responsive to future threats. But in other cases, it led to tolerance, where macrophages respond more weakly or slowly to a second exposure.
“Our results really underscored the complexity of immune signaling,” said Wang. “There are a lot of things going on and they all have different effects.”
There were no clear trends between the type of virus or bacteria and how immune signaling was changed. But in general, higher doses and longer exposures of a pathogen increased tolerance – which could be an adaptation to prevent the immune system from being overactivated, Wang said. Shorter exposures or lower doses often led to priming, making macrophages ready to respond to threats more aggressively.
When the team isolated macrophages from a mouse with sepsis – widespread inflammation that can follow a severe infection – they discovered that the cells had weaker than usual immune responses. The observation helps explain why patients with sepsis can be vulnerable to secondary infection. It also suggests that turning up macrophage activity – or blocking this “tolerance” – could help treat sepsis.