Immune Cells Require Ongoing Signals to Retain Memory of Past Infections

UCLA researchers discover that macrophages need persistent cytokine signaling to maintain enhanced immune response capabilities.

Published on Feb. 23, 2026

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Researchers from the University of California, Los Angeles, have discovered that immune cells called macrophages retain memories of previous infections through the persistent presence of signaling molecules left behind. The study, published in the Journal of Experimental Medicine, shows that these immune memory changes in macrophages are reversible and depend on ongoing cytokine signals, rather than being permanently encoded. This finding suggests new ways to potentially modify aberrantly trained macrophages that contribute to autoimmune diseases.

Why it matters

Understanding how macrophages maintain immune memory could lead to new therapies for autoimmune diseases like lupus and rheumatoid arthritis, where macrophages have become misprogrammed to attack the body's own healthy tissues. The reversible nature of macrophage immune memory also opens up the possibility of pharmacologically erasing or modifying these trained immune states.

The details

The researchers found that human macrophages temporarily exposed to the cytokine interferon gamma form thousands of new enhancer domains in their DNA that prime the cells for a stronger immune response to future threats. However, they discovered that small amounts of interferon gamma remain attached to the macrophages and their surrounding environment even after most of the cytokine has been removed. Signals from this residual interferon gamma are required to maintain the macrophages' memory - when the researchers inhibited these persistent cytokine signals, the macrophages erased their enhancers and reduced their response to bacterial molecules.

  • The study was published on February 18, 2026 in the Journal of Experimental Medicine.

The players

University of California, Los Angeles

The research was conducted by a team of researchers from this public research university in Los Angeles, California.

Alexander Hoffmann

The senior author of the study and a professor at the University of California, Los Angeles.

Aleksandr Gorin

The lead author of the study, an infectious disease physician and postdoctoral researcher in the Hoffmann laboratory.

Macrophages

Immune cells that patrol the body's tissues, engulf and kill threats like microbes or cancer cells, and send signals to other immune cells.

Interferon gamma

A signaling molecule or cytokine that prompts macrophages to form specialized enhancer domains in their DNA, priming them for a stronger immune response to future threats.

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What they’re saying

“Our new findings suggest that these changes in macrophages are actually readily reversible and do not inherently encode immune memory. Instead, the cells are dependent on ongoing signaling from interferon gamma sequestered at or near the macrophage cell surface.”

— Alexander Hoffmann, Senior Author (Journal of Experimental Medicine)

“We suggest that acute immune activity within a tissue in response to infection or injury may "stain" the tissue with cytokines and that ongoing signaling from these molecules contributes to lasting changes in tissue resident macrophages.”

— Aleksandr Gorin, Lead Author (Journal of Experimental Medicine)

“Our observation that the interferon gamma–induced memory state is pharmacologically reversible raises the possibility that at least some trained immune states can be pharmacologically erased or modified by blocking cytokine signaling pathways.”

— Alexander Hoffmann, Senior Author (Journal of Experimental Medicine)

What’s next

The researchers suggest that further study into blocking cytokine signaling pathways could lead to new therapies for autoimmune diseases where macrophages have become aberrantly trained.

The takeaway

This study provides important new insights into how the innate immune system retains memories of past infections, showing that macrophage immune memory is not permanently encoded but rather depends on ongoing cytokine signaling. This reversible nature of macrophage training opens up potential new avenues for modulating aberrant immune responses in autoimmune diseases.