Training the innate immune system to remember past threats

An international research team has shown how the innate immune system, which responds to general dangers detected in the body, can be trained to ‘remember’ past threats and respond more robustly to future challenges.

Published in the journal Cell, their findings point to a strategy by which one could prime the immune system prior to entering a situation where the risk of contracting an infection was high, or prior to receiving chemotherapy to avoid a depletion of the immune system’s neutrophils — some of the first cells to travel to points of infection.

Traditional vaccines enlist the adaptive immune system, the functions of which are carried out largely by hyperspecific T and B cells, each targeted to a particular threat. This is why a polio vaccine will prepare your immune system to defend against polio, but not chickenpox.

Until relatively recently, the dogma in immunology was that the adaptive immune system possesses a memory — which is why vaccines are effective even years later — while the innate immune system does not. In the last several years, however, studies by Mihai G Netea and others have shown that the innate immune system can be trained to have a robust response by challenging it with stimuli such as β-glucan, a sugar molecule found in fungus.

These initial investigations into innate immune training suggested that this effect was mediated by epigenetic changes to mature myeloid cells — the category of immune cells that encompasses neutrophils, monocytes, macrophages and others. But, because these mature cells survive only a day or two and the training effect can last months, Netea and his colleagues knew there had to be some other mechanism at work.

Their hypothesis was that the changes had to somehow affect the bone marrow, the site of haematopoietic stem cells (HSCs), and specifically those that serve as myeloid cell precursors. To test this prediction, they gave mice a single injection of β-glucan — and found that within a day their HSCs expanded in number.

“But it was not a random expansion,” said co-senior author George Hajishengallis, from the University of Pennsylvania. “There was a bias toward myelopoiesis” — that is, the generation of myeloid precursor cells.

What’s more, the team confirmed that the HSC changes were lasting. When they transplanted HSCs from mice that received either β-glucan or a control injection four weeks earlier into mice lacking HSCs, they found that the mice that received cells from the β-glucan group produced more cells of myeloid lineage.

To see if this myeloid cell expansion had a protective effect, the researchers challenged mice that had received β-glucan or a control with a substance that mimics a bacterial infection. They found that the β-glucan mice had a greater production of myeloid cells and less evidence of DNA damage in their HSCs compared to the control group.

The β-glucan challenge also had a beneficial impact after chemotherapy. While chemotherapeutics can deplete critical immune cells, the researchers found β-glucan stimulation resulted in mice having more white blood cells after treatment with two common chemotherapeutic drugs. These mice also lived longer than those that received a control injection.

“Taking β-glucan prior to chemotherapy would be a very good application,” said Hajishengallis. “And in the case of infections, β-glucan would activate your innate immune system so it would be poised to respond much faster and stronger to an infection.”

The researchers note that, despite the protective effects from infection and chemotherapy, there are reasons to be cautious about innate immune training. Amping up the innate immune system could cause an overabundance of inflammatory signalling, leading to problems such as tissue damage or autoimmune disease.

“All these mice treated with β-glucan were healthy to start and their immune systems were invigorated,” said Hajishengallis. “What we don’t know is what would happen if the mice already had a chronic condition or were older. Their immune systems could be poised to over-respond to perceived dangers and worsen a chronic inflammatory disease.”

The researchers plan to follow up on their work by looking at innate immune system training in the context of ageing and seeing how it affects the course of a variety of disease conditions, including the gum disease periodonditis — an area in which Hajishengallis has particular expertise.

Image caption: A macrophage extends arm-like projections to ‘eat’ two potential pathogens. The study found that the immune system could be trained to favour the production of macrophages and other myeloid cells upon encountering a challenge such as a pathogen or chemotherapy.