Immune cell memory may be stored in the folds of DNA

Immune cell memory may be preserved in the physical arrangement of DNA itself. Researchers have found that an initial immune signal can reorganize the chromosomes of macrophages, creating new contacts that persist after the signal disappears. When the cells encounter a different stimulus later, some genes respond much more strongly.

One inflammatory gene offered a particularly striking example. Its activity barely changed after the first signal, and the usual epigenetic markers showed no detectable remodeling. Yet 24 hours later, the gene responded much more strongly to a second stimulus.

The missing record of the first exposure was found in the three-dimensional architecture of the genome.

More than a thousand new contacts in one day

In a study published in PNAS, researchers examined mouse macrophages, immune cells that engulf pathogens, clear cellular debris and coordinate inflammatory responses.

They first exposed the cells to interleukin-4 (IL-4) for 24 hours. IL-4 is an immune signaling protein that shifts macrophages into a particular functional state.

The researchers then removed the cytokine, allowed the cells to rest for another 24 hours and examined which changes remained.

The first exposure produced 1,155 new chromatin loops. Of these, 460 — approximately 40% — persisted after the cytokine was withdrawn. Another 345 contacts became strongest after its removal.

To understand why these changes matter, it helps to consider how DNA is organized inside the nucleus.

Chromosomes are not straight strands. They fold repeatedly, creating loops that bring distant regions of DNA into physical proximity.

This folding is essential for gene regulation.

Each gene has a promoter, where the machinery responsible for reading genetic information assembles. Other DNA regions, known as enhancers, can boost gene activity. Chromatin looping can bring enhancers close to their target promoters, allowing them to influence gene expression.

IL-4 was changing precisely these interactions.

The gene remains quiet, but its next response changes

The inflammatory gene Il6 provides one of the clearest examples.

Il6 encodes interleukin-6, an important regulator of inflammatory responses. Following IL-4 exposure, the researchers detected no increase in its baseline expression and no significant local changes in chromatin accessibility or conventional histone modifications.

Its three-dimensional configuration, however, had changed.

The Il6 promoter established a new interaction with a regulatory element located approximately 64,000 DNA bases upstream. This chromatin loop remained in place after IL-4 was removed.

When the macrophages later encountered lipopolysaccharide, a bacterial component that triggers inflammatory signaling, Il6 expression increased more strongly than it otherwise would.

The initial signal had effectively positioned a distant regulatory element near the gene before the gene itself became more active.

Using CRISPR to disrupt the regulatory element weakened the enhanced response to subsequent stimulation.

Experiments involving another gene, F10, also showed that both regulatory elements and structural regions involved in organizing chromatin loops were necessary for the enhanced response.

Another layer of cellular memory

The changes extended well beyond a single gene.

Following IL-4 exposure, the macrophages showed enhanced transcriptional responses to several different secondary signals, including bacterial endotoxin, interferon-gamma and dexamethasone.

For endotoxin alone, the researchers identified 849 genes with enhanced responses.

The central finding is that changes in genome architecture could persist even when there were no detectable accompanying changes in baseline transcription, chromatin accessibility or conventional histone modifications.

Those epigenetic mechanisms have traditionally been considered major contributors to cellular memory.

The new findings reveal another potential layer: the three-dimensional organization of chromosomes.

There are important limitations. The experiments were performed primarily in mouse bone marrow-derived macrophages, and the memory response was examined 24 hours after withdrawal of the initial stimulus. The findings do not establish how long these structures persist in living organisms or whether the same mechanism contributes to chronic inflammatory disease in humans.

There is also a mechanistic distinction that remains unresolved. CRISPR disruption of regulatory regions can affect both their intrinsic enhancer activity and their three-dimensional interactions, making it difficult to separate the two effects completely.

Nevertheless, the experiments establish that immune cells can preserve information about prior stimulation through changes in genome architecture and that these changes contribute to their response to a later signal.

A macrophage can prepare for its next challenge by bringing the right pieces of DNA closer together before the relevant genes are activated.