Scientists discover how life experiences rewrite the immune system
The COVID-19 pandemic made one thing unmistakably clear: people can experience the same infection in dramatically different ways. Some develop mild symptoms, while others face severe illness. This wide range of outcomes raises a fundamental question. Why do two people exposed to the same pathogen respond so differently?
A major part of the answer lies in differences in genetics (the genes you inherit) and life experience (your environmental, infection, and vaccination history). These factors influence how cells behave through subtle chemical changes known as epigenetic modifications. These molecular changes help determine which genes are active or silent, shaping how cells function without altering the underlying DNA sequence.
Researchers at the Salk Institute have now created a detailed epigenetic catalog that shows how inherited traits and life experiences affect different immune cell types in distinct ways. The cell type-specific database, published in Nature Genetics on January 27, 2026, offers new insight into why immune responses vary so widely between individuals. It also points toward future treatments that could be tailored to each person’s unique biology.
“Our immune cells carry a molecular record of both our genes and our life experiences, and those two forces shape the immune system in very different ways,” says senior author Joseph Ecker, PhD, professor, Salk International Council Chair in Genetics, and Howard Hughes Medical Institute investigator. “This work shows that infections and environmental exposures leave lasting epigenetic fingerprints that influence how immune cells behave. By resolving these effects cell by cell, we can begin to connect genetic and epigenetic risk factors to the specific immune cells where disease actually begins.”
What the Epigenome Is and Why It Matters
Every cell in the human body contains the same DNA. Yet cells can look and act completely differently, depending on their role. This diversity is partly driven by epigenetic markers, small molecular tags attached to DNA that help control which genes are switched on or off in each cell. Together, all of these markers make up a cell’s epigenome.
Unlike DNA itself, the epigenome can change over time. Some epigenetic patterns are strongly influenced by inherited genetic differences, while others are shaped by experiences throughout life. Immune cells are affected by both forces, but until now, scientists did not know whether inherited and experience-based epigenetic changes shaped immune cells in the same way.
“The debate between nature and nurture is a long-standing discussion in both biology and society,” says co-first author Wenliang Wang, PhD, a staff scientist in Ecker’s lab. “Ultimately, both genetic inheritance and environmental factors impact us, and we wanted to figure out exactly how that manifests in our immune cells and informs our health.”
How Life Experiences Leave a Molecular Mark on Immune Cells
To untangle the effects of genetics and experience, the research team analyzed blood samples from 110 people with diverse backgrounds. These samples reflected a wide range of genetic variation and life exposures, including flu; HIV-1, MRSA, MSSA, and SARS-CoV-2 infections; anthrax vaccination; and exposure to organophosphate pesticides.
The scientists examined four major immune cell types. T cells and B cells are known for retaining long-term immune memory, while monocytes and natural killer cells respond quickly to threats. By comparing epigenetic patterns across these cells, the team built a comprehensive catalog of epigenetic markers, also called differentially methylated regions (DMRs), for each immune cell type.
“We found that disease-associated genetic variants often work by altering DNA methylation in specific immune cell types,” says co-first author Wubin Ding, PhD, a postdoctoral fellow in Ecker’s lab. “By mapping these connections, we can begin to pinpoint which cells and molecular pathways may be affected by disease risk genes, potentially opening new avenues for more targeted therapies.”
Separating Inherited and Experience-Driven Epigenetic Changes
A key advance of the study was the ability to distinguish epigenetic changes tied to genetics (gDMRs) from those linked to life experiences (eDMRs). The researchers found that these two types of markers tend to appear in different parts of the epigenome. Genetically inherited changes were more often found near stable gene regions, particularly in long-lived T and B cells. In contrast, experience-related changes were concentrated in flexible regulatory regions that control rapid immune responses.
These patterns suggest that genetics helps establish long-term immune programs, while experiences fine-tune how immune cells react to specific situations. More research will be needed to fully understand how these influences affect immune performance in health and disease.
“Our human population immune cell atlas will also be an excellent resource for future mechanistic research on both infectious and genetic diseases, including diagnoses and prognosis,” says co-first author Manoj Hariharan, PhD, a senior staff scientist in Ecker’s lab. “Often, when people become sick, we are not immediately sure of the cause or potential severity — the epigenetic signatures we developed offer a road map to classify and assess these situations.”
Toward Predicting Disease Outcomes and Personalizing Care
The findings highlight how powerfully both genetics and life experience shape immune cell identity and immune system behavior. The new catalog also provides a starting point for designing more personalized approaches to treatment and prevention.
Ecker notes that as the database grows with additional patient samples, it could help predict how individuals might respond to future infections. For instance, if enough COVID-19 patients contribute data, researchers might discover that survivors share a common protective eDMR. Doctors could then analyze a newly infected patient’s immune cells to see whether that protective marker is present. If it is missing, scientists could potentially target related regulatory pathways to improve outcomes.
“Our work lays the foundation for developing precision prevention strategies for infectious diseases,” says Wang. “For COVID-19, influenza, or many other infections, we may one day be able to help predict how someone may react to an infection, even before exposure, as cohorts and models continue to expand. Instead, we can just use their genome to predict the ways the infection will impact their epigenome, then predict how those epigenetic changes will influence their symptoms.”
Authors and Funding
Other authors include Anna Bartlett, Cesar Barragan, Rosa Castanon, Vince Rothenberg, Haili Song, Joseph Nery, Jordan Altshul, Mia Kenworthy, Hanqing Liu, Wei Tian, Jingtian Zhou, Qiurui Zeng, and Huaming Chen of Salk; Andrew Aldridge, Lisa L. Satterwhite, Thomas W. Burke, Elizabeth A. Petzold, and Vance G. Fowler Jr. of Duke University; Bei Wei and William J. Greenleaf of Stanford University; Irem B. Gündüz and Fabian Müller of Saarland University; Todd Norell and Timothy J. Broderick of the Florida Institute for Human and Machine Cognition; Micah T. McClain and Christopher W. Woods of Duke University and Durham Veterans Affairs Medical Center; Xiling Shen of the Terasaki Institute for Biomedical Innovation; Parinya Panuwet, and Dana B. Barr of Emory University; Jennifer L. Beare, Anthony K. Smith, and Rachel R. Spurbeck of Battelle Memorial Institute; Sindhu Vangeti, Irene Ramos, German Nudelman, and Stuart C. Sealfon of Icahn School of Medicine at Mount Sinai; Flora Castellino of the US Department of Health and Human Services; and Anna Maria Walley and Thomas Evans of Vaccitech plc.
The work was supported by the Defense Advanced Research Projects Agency (N6600119C4022) through the US Army Research Office (W911NF-19-2-0185), National Institutes of Health (P50-HG007735, UM1-HG009442, UM1-HG009436, 1R01AI165671), and National Science Foundation (1548562, 1540931, 2005632).
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