Why can two people encounter the same infection but experience very different symptoms? Age, health, previous infections, vaccination history, and genetics can all influence the immune response. A study published in Nature Genetics suggests that genetics and life experiences are also associated with distinct molecular patterns across the epigenomes of our immune cells.
Researchers at the Salk Institute analyzed immune cells from 110 people to investigate how genetic variation and environmental experiences influence DNA methylation and chromatin accessibility. Their findings provide an atlas showing that “nature” and “nurture” are associated with different regions of the immune-cell epigenome.
The Epigenome: Where Genes Meet Experience
Most cells contain essentially the same DNA sequence, yet a T cell behaves very differently from a neuron or muscle cell. These differences are controlled partly by the epigenome, a collection of molecular features that helps determine which genes are available for use.
One of the best-studied epigenetic mechanisms is DNA methylation, in which methyl groups are added to DNA. Depending on where methylation occurs, it can influence whether nearby genes are active. Chromatin accessibility also matters: open chromatin allows regulatory proteins to reach DNA more easily, while tightly packed chromatin can make genes less accessible.
As senior author Joseph Ecker, PhD, explained, “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.” Infections and environmental exposures may leave lasting epigenetic changes that influence how immune cells function. By examining these changes in individual cell types, researchers may be able to identify which immune cells are involved in the earliest stages of disease.
Building an Atlas of Human Immune Cells
The researchers examined 171 blood samples from 110 individuals with different genetic backgrounds and exposure histories. These included people with histories of influenza A, HIV-1, SARS-CoV-2, Staphylococcus aureus infection, anthrax vaccination, or organophosphate pesticide exposure. The work builds on earlier research into the epigenetics of influenza and why COVID-19 can affect people differently.
The team separated the samples into immune-cell populations, including naïve and memory T cells, B cells, natural killer cells, and monocytes. Using single-nucleus DNA methylation sequencing and single-cell ATAC-seq, they examined methylation and chromatin accessibility within individual cell types.
This cell-by-cell approach mattered because an epigenetic change in a monocyte may not have the same function—or may not appear at all—in a T cell. It also helped researchers compare fast-acting immune cells with T and B cells involved in immune memory.
Nature and Nurture Leave Marks in Different Places
The researchers identified exposure-associated differentially methylated regions, or eDMRs, where DNA methylation was associated with environmental experiences. They also identified genotype-associated differentially methylated regions, or gDMRs, linked to inherited genetic variants. A gDMR does not necessarily mean that the methylation mark itself was inherited. Rather, it means that a person’s inherited DNA sequence was associated with the methylation pattern found in that region.
The two categories appeared in different parts of the genome. Exposure-associated changes were enriched in enhancers and other flexible regulatory regions that help cells activate specific responses. Genotype-associated patterns occurred more often in gene bodies and regions connected with stable cellular programs.
Together, these findings suggest that genetics and experience shape immunity through different regulatory routes. Genetic variation may have a stronger influence on stable, long-term aspects of immune-cell identity, particularly in memory T and B cells. Environmental exposures, meanwhile, were more strongly associated with dynamic regulatory regions that help immune cells adjust during infection or other challenges.
Connecting Disease Risk to Specific Immune Cells
The researchers also compared their atlas with genetic variants associated with disease. Many disease-linked variants overlapped with variants connected to DNA methylation, but these relationships were often limited to particular immune-cell types.
For example, the study identified cell-specific links among eczema-associated genetic variants, DNA methylation, and nearby gene regulation. Pinpointing the affected cell type could help researchers identify the immune cells and pathways most likely to contribute to disease.
Could Epigenetic Profiles Predict Immune Responses?
The atlas is not yet a clinical test, but it provides a framework for investigating why people respond differently to infections, vaccines, and treatments. With larger datasets, researchers may eventually identify epigenetic signatures associated with protection, severe illness, treatment response, or recovery.
Some exposure groups included relatively few participants, and before-and-after samples were not available for every exposure. Larger studies following people over time will be needed to determine when these differences develop, how long they persist, and whether particular exposures directly cause them.
Still, the findings offer a more detailed view of the nature-versus-nurture question. Genes and life experiences appear to influence different parts of the epigenetic machinery, working together to shape how immune cells develop, remember, and respond.
Source: Wenliang Wang, et al. Genetics and environment distinctively shape the human immune cell epigenome. Nature Genetics, January 27, 2026.
Reference: How do nature and nurture shape our immune cells? Salk Institute. January 27, 2026
