With the onset of the COVID-19 pandemic, it became clear that people respond differently to the same infection. Some exhibit mild symptoms, while others experience serious complications. This discrepancy raises an important question: why do two individuals exposed to the same virus react differently?
The key to the answer lies in the differences present in both the genetic information and life experiences of each person, including environmental factors, past infections, and vaccinations. These elements influence the behavior of immune cells through epigenetic modifications—molecular changes that determine gene activity without altering the DNA itself.
A team of scientists from the Salk Institute has developed an extensive epigenetic catalog that demonstrates how hereditary and life factors affect different types of immune cells. The database, published on January 27, 2026, in the journal Nature Genetics, provides new insights into why immune responses vary among individuals and points to opportunities for developing new drugs tailored to the individual biology of each patient.
“Immune cells carry a molecular trace of both our genes and our life experiences. These two aspects shape the immune system in different ways,” explains senior author of the study Joseph Ecker, professor and chair of the Department of Genetics at the Salk Institute. “Our work shows that infections and environmental factors leave a lasting epigenetic mark that influences the behavior of immune cells. By deciphering this influence, we can better understand the genetic and epigenetic risk factors for specific immune system cells, which is important for studying diseases.”
What is the epigenome and its significance
All cells in the human body contain identical DNA; however, cells can differ in appearance and function. This diversity is partly determined by epigenetic markers—molecular tags that help regulate gene activity in each cell. All these markers collectively make up the epigenome.
The epigenome is subject to changes throughout life. Some epigenetic characteristics are inherited, while others are shaped by life experiences. The influence of these factors on immune system cells was unknown until recently.
“The debate about heredity and environment is a long-standing question in both biology and society,” notes first author of the study Wenliang Wang. “We wanted to find out how these two elements manifest in immune system cells and affect health.”
How life experience affects immune system cells
To study the influence of genetics and life experience, researchers analyzed blood samples from 110 patients that reflected a wide range of genetic variations and life experiences, including infections and vaccinations. The scientists examined four main groups of immune system cells: long-term memory T cells and B cells, as well as monocytes and natural killer cells that respond to threats.
By comparing the epigenetic data in these groups, the team compiled a catalog of epigenetic markers known as differentially methylated regions (DMRs) for each type of immune cell.
“We found that genetic variants associated with diseases often affect DNA methylation in specific types of cells,” adds first author of the study Ubin Ding. “By creating a map of these relationships, we can more accurately identify which cells and molecular pathways may be affected by genes associated with diseases, opening new avenues for targeted therapies.”
Distinguishing epigenetic changes
One of the main findings of the study was the distinction between epigenetic changes related to genetics (gDMR) and those that depend on life experience (eDMR). Researchers noted that these two types of markers manifest in different areas of the epigenome. Genetically inherited changes are more commonly found in stable regions of genes, while changes related to life experience are concentrated in flexible regulatory regions responsible for rapid immune responses.
These observations suggest that genetics sets long-term programs for the immune system, while life experience fine-tunes the response of cells to specific circumstances. Further research is needed for a deeper understanding of how these factors influence immune response in health and disease.
“Our atlas of immune cells will be a valuable resource for future research, both on infectious and genetic diseases,” emphasizes Manoj Hariharan, a senior researcher in Ecker's lab. “Often, we cannot immediately determine the cause of a disease and its severity—our epigenetic markers can serve as a guide for classifying and assessing these situations.”
Prospects for disease prediction and personalized medicine
The results of the study demonstrate the significant impact of both genetic and life factors on the identity of immune system cells. The new catalog could serve as a foundation for creating a more personalized approach to disease treatment and prevention.
Ecker notes that as the database of new samples from patients grows, it may help predict responses to future infections. For example, by analyzing data from COVID-19 patients, researchers can identify common protective eDMRs in those who have already recovered from the infection. This will allow doctors to assess the immune cells of newly infected individuals and check for the presence of protective markers. If absent, scientists can target appropriate regulatory pathways to improve treatment outcomes.
“Our work lays the groundwork for developing highly precise methods for preventing infectious diseases,” concludes Wang. “We will be able to predict a person's response to an infection even before it occurs if cohorts and models continue to grow. Instead, we can use the genome to predict how an infection will affect the epigenome and then assess how these changes will impact symptoms.”
The study was supported by the Defense Advanced Research Projects Agency (DARPA), the National Institutes of Health, and the National Science Foundation.
