Repeated interferon stimulation creates innate immune memory

October 25, 2018, Hokkaido University
Cell survival under different pretreatment conditions. IFN-pretreated cells (top) have a higher chance of surviving a viral (EMCV) infection than naïve (untreated) cells (bottom). Left: mock infection. Middle: viral infection without IFN re-stimulation. Right: Viral infection with IFN re-stimulation 2h before infection. Credit: Kamada R. et al., PNAS, September 25, 2018

Mammalian cells seem to be able to memorize anti-viral stimulation at the level of DNA-packaging molecules, enabling faster and greater activation of anti-viral genes in subsequent stimulations, according to a study conducted by Hokkaido University Assistant Professor Rui Kamada and Dr.Keiko Ozato of the National Institutes of Health. Kamada explains: "This is the first time that the adaptive immune system was shown to exhibit a memory in gene regulation, and that involves DNA binding to variant packaging proteins."

Vertebrates have two systems helping them fend off infections. The adaptive immune system is known to "learn" and "remember" the shape of infecting agents. This is the system that vaccines use to confer immunity, by introducing the body to a pathogen's structure. The older part of the immune system, the innate immune system, has several functions. For example, it causes the symptoms of inflammation that enable the body to clear invading or damaged . Another important function of this system is mediated by interferons, signaling molecules that cells release when they are infected by viruses to induce their neighbors to produce antiviral defenses. However, the innate immune system is not usually thought to have any of prior infections.

In the study published in the Proceedings of the National Academy of Sciences, Kamada and her group exposed fibroblasts derived from mouse embryos, a typical cell model for this kind of study, to interferons repeatedly. "To our surprise, we found that for about 1,000 genes the response to the second exposure was markedly faster and greater than to the first one. Another 1,000 genes did not show a different response to the second interferon stimulation, or were not any longer activated," says Professor Kamada. Based on these data, the researchers inferred there is specific memory in the innate immune system.

Schematic of the interferon-stimulated memory effect. Untreated cells (naïve cells), upon exposure to interferons, read memory interferon-stimulated genes (ISGs) that are wrapped around standard histones (yellow cylinders). This leads to their becoming “pretreated cells” and the swapping of the standard histones for variants (green cylinders) as well as the histones’ modification (pink and blue pins). At subsequent interferon exposures, reading of ISGs is stronger and commences more quickly. Credit: Hokkaido University

Stepwise exclusion of other possibilities enabled the researchers to prove that the cause for this memory is a change in the use of DNA-packaging molecules. DNA is wrapped around proteins called histones, and the variety of histones and their modification determine whether or not a certain stretch of DNA can be accessed quickly. After the first encounter of interferons, the fibroblasts swapped the type of histones around which the roughly 1,000 up-regulated genes are wrapped, enabling these to be activated faster. The group showed that this modification was conserved even through multiple cell divisions.

There had been some previous indications that the innate immune system might after all contribute to some . However, this study is the first to provide a clear mechanistic explanation for a trained , namely a change in DNA packaging by histones.

Explore further: How our immune system detects broken DNA

More information: Rui Kamada et al. Interferon stimulation creates chromatin marks and establishes transcriptional memory, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1720930115

Related Stories

How our immune system detects broken DNA

September 6, 2018
Our immune system is working every day to protect us from bacteria, viruses, and parasites, but it can also detect when our own cells are damaged.

Curing diseases with good bacteria

October 15, 2018
Researcher from the Institute of Biology, Leiden have discovered how good intestinal bacteria regulate our innate immune system. This surprising discovery could make it possible to treat diseases related to inflammation, ...

The STING of death in T cells

September 5, 2017
The cells of the innate immune system use a signaling pathway comprising STING (Stimulator of interferon genes) to detect DNA from invading viruses and fight them. However, it is unknown if STING triggers the same or different ...

How the human body first fights off pathogens

July 24, 2017
People constantly encounter viruses, bacteria or parasites. Fortunately, our skin, the specialized lining of our guts and other parts of our body that are exposed to the outside world prevent them from entering. When a pathogen ...

New study links gray hair with immune system activity and viral infection

May 3, 2018
A new study on mice offers insights into why some people's hair may turn gray in response to a serious illness or chronic stress. Publishing May 3 in the open access journal PLOS Biology, researchers at the National Institutes ...

Recommended for you

Study reviews what causes chronic itching and scratching

November 21, 2018
Relentless itch is a feature of many skin disorders, such as eczema and psoriasis, but the cause of this itch—and what drives us to scratch—is somewhat mysterious. A review appearing November 21 in the journal Trends ...

Regulating the immune system's 'regulator'

November 20, 2018
A research team at the Academy of Immunology and Microbiology, within the Institute for Basic Science (IBS) has discovered a possible therapeutic target that pulls the reins of immunity. In Nature Communications, the scientists ...

New immunotherapy improves MS symptoms

November 20, 2018
A world-first clinical trial of a new cellular immunotherapy for multiple sclerosis (MS) has improved symptoms and quality of life for the majority of patients.

Scientists unveil completely human platform for testing age-specific vaccine responses

November 20, 2018
A team of scientists at Boston Children's Hospital has developed the first modeling system for testing age-specific human immune responses to vaccines—outside the body. The practical, cost-effective new platform, using ...

To resolve inflammation, location matters

November 19, 2018
Health conditions that involve inflammation run the gamut, from multiple sclerosis and lupus to arthritis, diabetes, and cancer. While inflammation can serve as a normal response to help the body deal with injury or infection, ...

New insights into how an ordinary stem cell becomes a powerful immune agent

November 19, 2018
How do individual developing cells choose and commit to their "identity"—to become, for example, an immune cell, or a muscle cell, or a neuron?

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.