Epigenetic Switch in Blood Cells Boosts Immune Response

Scientists at the German Cancer Research Center (DKFZ) have discovered an epigenetic switch in blood stem cells and progenitor cells that can trigger the change from normal to emergency mode during infections. Their work, published in the journal Science Immunology, could lead to new ways of boosting the body's immune response to infections and improving the defense against pathogens.

The emergency program of hematopoiesis signals an alarm state in the immune system and has two key purposes. Firstly, it increases the replenishment of immune cells consumed during infections or inflammations. Secondly, it puts the immune system into a pre-activation state that helps clear infections more quickly.

The emergency program is characterized by an increased division rate of blood stem cells and a shift in the balance of mature white blood cells in favor of myeloid cells, such as macrophages and granulocytes. Typically, the emergency program is triggered by molecular components of pathogens or by pro-inflammatory messenger substances like interferons.

But what happens in the blood stem cells and progenitor cells to trigger the emergency program? The scientists, led by Nikolaus Dietlein and Hans-Reimer Rodewald, targeted a specific epigenetic modification called H2Bub1. This modification is involved in switching on genes that are activated by interferon in response to viral infection and are important for defense against infection. H2Bub1 attaches to the packaging proteins of DNA, known as histones, and is removed again by the enzyme USP22.

The researchers wondered if H2Bub1 and USP22 could be the sought-after switch that triggers the emergency program in blood stem cells. To find out, they switched off USP22 in mice's blood stem cells. In these animals, the emergency program of hematopoiesis ran without any detectable infection or increased interferon levels.

The genetically modified mice were better able to fight off infection with the bacterium Listeria monocytogenes than normal mice. Additionally, scavenger cells in their blood, such as neutrophil granulocytes, were more successful at engulfing bacteria.

As expected, the genetic material in the blood cells of the genetically modified animals also had significantly more epigenetic H2Bub1 modifications. This suggests that the increased H2Bub1 level acts as an alarm button that puts the immune system on standby, particularly the innate immune defense, which is crucial during initial contact with a pathogen. USP22, which removes the H2Bub1 modification, ends the alert in normal animals.

"The increased H2Bub1 level seems to be the alarm button that puts the immune system on standby. In particular, this puts the innate immune defense, which is especially important during initial contact with a pathogen, into heightened defense alert," says first author Nikolaus Dietlein.

"In mice, we were able to show that an epigenetic modification improves the defense against infection," explains senior author Hans-Reimer Rodewald of the German Cancer Research Center. "However, how the loss of USP22 affects human hematopoietic stem and progenitor cells is still unknown and should now be investigated. Inhibition of USP22 by drugs could possibly one day help to improve the immune defense against pathogens. So far, however, this is currently still unproven and needs to be tested in further studies."