New Epigenetic Catalog Helps Explain Individual Differences in Immune Responses

The COVID-19 pandemic gave us tremendous perspective on how wildly symptoms and outcomes can vary between patients experiencing the same infection. How can two people infected by the same pathogen have such different responses?

It largely comes down to variability in genetics (the genes you inherit) and life experience (your environmental, infection, and vaccination history). These two influences are imprinted on our cells through small molecular alterations called epigenetic changes, which shape cell identity and function by controlling whether genes are turned "on" or "off."

Salk Institute researchers are debuting a new epigenetic catalog that reveals the distinct effects of genetic inheritance and life experience on various types of immune cells. The new cell type-specific database, published in Nature Genetics on January 27, 2026, helps explain individual differences in immune responses and may serve as the foundation for more effective and personalized therapeutics.

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. 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."

Joseph Ecker, PhD, senior author, professor, Salk International Council Chair in Genetics, and Howard Hughes Medical Institute investigator

What is the Epigenome?

All the cells in your body share the same DNA sequence. And yet, there are many specialized cell types that look and act entirely differently. This diversity is due, in part, to a collection of small molecular tags called epigenetic markers, which decorate the DNA and signal which genes should be turned on or off in each cell. The many epigenetic changes in each cell collectively make up that cell's epigenome.

Unlike the base genetic code, the epigenome is far more flexible-some epigenetic differences are strongly influenced by inherited genetic variation, while others are acquired experientially across a lifetime. Immune cells are no exception to these forces, but it was unclear whether these two types of epigenetic changes-inherited versus experiential-affected 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 Do Your Life Experiences Affect Your Immune Cells?

To determine how nature and nurture influence immune cell epigenomes, the Salk team needed to survey a diverse pool of samples. By collecting and analyzing blood samples from 110 individuals, the researchers were able to observe the effects of a variety of genetic profiles and life experiences, including flu; HIV-1, MRSA, MSSA, and SARS-CoV-2 infections; anthrax vaccination; and exposure to organophosphate pesticides.

The researchers then compared the epigenetic profiles of four major immune cell types: T and B cells, known for their long-term memory of past infections, and monocytes and natural killer cells, which respond more broadly and rapidly. From these many samples and cells, the team built a catalog of all the epigenetic markers, or differentially methylated regions (DMRs), in each 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."

Importantly, the researchers were able to parse out which epigenetic changes were genetically inherited (gDMRs) and which were from life experiences (eDMRs). It became clear that gDMRs and eDMRs were clustered in distinct regions of the epigenome, with gDMRs occurring around more stable gene regions-especially in long-lived T and B cells-and eDMRs primarily in flexible regulatory regions that trigger specific immune responses.

Based on the variable gDMR and eDMR locations, the data suggest that genetic inheritance shapes more stable, long-term immune programs, while life experiences preferentially influence dynamic, context-specific immune responses. Further research will need to elucidate the exact impact that nature-versus-nurture factors have on immune performance.

"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."

Could We Use Immune Cell Epigenomes to Predict Patient Outcomes?

The findings demonstrate the unique and substantial influence of both nature and nurture on immune cell identity and immune system performance. What's more, the catalog offers an exciting jumping-off point for creating new personalized treatment plans.

Ecker explains that with more time and more patient samples, this catalog could serve as a blueprint for predicting how someone may respond to an infection. For example, if enough COVID-19 patients contribute their immune cells to the database, researchers could find survivors all share the same eDMR. From there, scientists could profile a new COVID-19 patient to see whether they already have this protective eDMR, and if not, they could identify protective regulatory mechanisms associated with that eDMR and target them therapeutically.

"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."