The immune system is one of the most complex parts of our body. It keeps us healthy by getting rid of parasites, viruses or bacteria and destroying damaged or cancerous cells. One of its most intriguing abilities is its memory: the first time it is in contact with a foreign component (called “antigen” in scientific jargon) our adaptive immune system takes about two weeks to respond, but in subsequent contacts its responses are much faster, as if the cells “remembered” the antigen. But how do they get this memory?
In a recently published study, a team of researchers coordinated by Dr. Ralph Stadhouders, from the Rotterdam University Medical Center in the Netherlands, and Dr. Grégoire Stik, Group Leader at the Josep Carreras Leukemia Research Institute in Badalona, Barcelona, provides new clues about immune memory using cutting-edge methodologies.
In their research paper, Anne Onrust-van Schoonhoven, as first author, and her colleagues compared the response of immune cells that had never been in contact with an antigen (called naïve cells) with that of cells that had previously been exposed to the antigen. (cells with memory) and that, in a way, they knew it. They focused on differences in epigenetic control of cellular machinery and the nuclear architecture of cells, two mechanisms that could explain the rapid pattern of activation of memory cells.
Although all of an individual’s cells have the same genetic information, each cell type accesses different parts of the DNA. The term “epigenetics” encompasses the mechanisms that dynamically control this access. The research team’s results revealed a particular epigenetic signature in memory cells, which causes rapid activation of a crucial set of genes when compared to naïve cells. These genes are much more accessible to the cellular machinery, in particular to a family of transcription factors called AP-1.
However, this epigenetic signature is just the tip of the iceberg. It is known that the position of DNA in the nucleus is not random and reflects the state of activation of the cell. The researchers found that indeed the three-dimensional distribution of DNA in the nucleus is different between naïve and memory immune cells. The key genes of the rapid immune response are clustered together and under the influence of the same regulatory regions, called enhancers.
Dr. Gregoire Stik. (Photo: Josep Carreras Leukemia Research Institute)
Although most of the research has focused on healthy cells, the scientific team wondered if any of the discovered mechanisms could, when altered, explain real diseases in which the immune system plays an important role. To answer this question, they analyzed immune cells from patients with chronic asthma and found that circuits identified as key to a fast and strong immune response were overactivated.
Epigenetic control of the immune system is an expanding field, and discoveries like those of Dr. Stik and his colleagues are paving the way for the next generation of epigenetic drugs and treatments targeting autoimmune diseases and cancer.
The study is titled “3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction”. And it has been published in the academic journal Science Immunology. (Source: Josep Carreras Leukemia Research Institute)