How DNA and life experiences leave distinct marks on the human immune system

A high-resolution immune cell atlas reveals how inherited DNA and life-long environmental exposures leave separate epigenetic signatures that together program immune function and disease risk.

Study: Genetics and environment distinctively shape the human immune cell epigenome. Image Credit: Anusorn Nakdee / Shutterstock

In a recent study published in Nature Genetics, researchers created a comprehensive atlas to elucidate the combined impacts of genetic inheritance and environmental exposures on the human immune system. The study analyzed blood samples from 110 donors exposed to pathogens, such as HIV and COVID-19, or chemicals, such as pesticides, and found that environmental and genetic factors target different parts of the genome.

Specifically, while genetic factors primarily influence the gene bodies in memory immune cells, environmental factors tend to tweak the regulatory “switches”, enhancers, and promoters in naive immune cells. These findings offer a high-resolution map of how infection history and underlying DNA combine to shape immune cell states and functions relevant to human health, with epigenetic changes frequently aligning with altered chromatin accessibility in regulatory regions.

Background: Nature, Nurture, and Immune Plasticity

Traditional wisdom held that environmental exposures determined an individual’s long-term health outcomes. The discovery of genetics and DNA shifted this wisdom into a debate over the relative importance of nature, genetics, nurture, and environment in human development.

Scientists agree that one of the most important models of the interplay between genetics and the environment is that of the immune system, which must be rigid enough to distinguish self from non-self, yet flexible enough to learn from new threats.

Previous studies have long established that the DNA sequence is inherited and unchangeable. However, more recent research posits that the way those genes are used is controlled by the epigenome. The epigenome is the mechanistic interaction between genetics and the environment that results in altered gene expression without altering the underlying DNA sequence.

Epigenetic Regulation and DNA Methylation

One of the primary tools the epigenome uses is DNA methylation, the addition of chemical tags, methyl groups, to DNA that act like dimmer switches, increasing or reducing gene expression without changing the underlying code. While previous research has investigated the effects of environmental exposures on epigenetic outcomes, it has focused mainly on bulk tissue, thereby obscuring the fine details of how specific immune cell types and states respond.

Study Design and Sample Population

The present study aimed to address the limitations of previous research and expand scientific understanding of immune health by analyzing 171 peripheral blood mononuclear cell (PBMC) samples from 110 individuals.

The sample cohort comprised both healthy donors and individuals with specific, defined exposures.

For HIV-1 and IAV, we have internal control samples that are from the same set of donors before infection and collected samples from them after exposure. We also collected PBMC from 12 healthy donors as external controls. For exposures without internal controls (COVID, anthrax vaccine, MRSA/MSSA and OP), all healthy samples were used as controls. We performed snATAC–seq and snmC-seq2 on the PBMCs and identified the eDMRs associated with exposures and genotypes. We also identified the gDMRs using this dataset. BA, B. anthracis. The figure is created with BioRender.com.

Types of Environmental and Biological Exposures

• Viral infections, including HIV-1, Influenza A (IAV), and SARS-CoV-2 (COVID-19).

• Bacterial infections such as Methicillin-resistant Staphylococcus aureus (MRSA) and MSSA.

• Chemical or vaccine exposures, specifically organophosphate pesticides (OPs) and the anthrax vaccine.

Experimental Methods and Cell-Type Resolution

Experimental assays included snmC-seq2 library preparation, enabling sequencing of DNA methylation in single-cell nuclei. Participants’ blood samples were sorted into seven major immune cell types, including T cells, B cells, natural killer (NK) cells, and monocytes. Downstream analyses further resolved these populations into naive and memory lymphocyte states, as well as additional immune subtypes.

Longitudinal and Comparative Analyses

Longitudinal internal controls were available for HIV-1 and Influenza A virus exposures, where donors were sampled before and after infection. Other exposure analyses relied on external controls and statistical adjustment and were therefore more limited in their ability to capture within-individual epigenetic change.

By comparing these groups against controls, the study’s statistical analyses sought to elucidate exposure-associated differentially methylated regions (eDMRs) and genotype-associated differentially methylated regions (gDMRs).

Epigenetic Signatures of Exposure and Inheritance

• eDMRs, exposure-associated differentially methylated regions, changes associated with environmental exposures.

• gDMRs, genotype-associated differentially methylated regions, changes associated with inherited genetic variation.

Key Findings: Genome-Wide Epigenetic Mapping

The study’s snmC-seq2 analysis identified 756,575 environmental methylation markers (eDMRs) and over 275,000 genetic markers (gDMRs) across the investigated immune cell types. The analysis’s most notable finding was that nature and nurture appear to operate on different genomic “territory”.

Distinct Genomic Targets of Genetic and Environmental Effects

Distinct genomic targets, eDMRs were consistently enriched in enhancer- and promoter-associated regulatory regions, the genomic switches that influence when genes are turned on or off. In contrast, gDMRs were predominantly located within gene bodies. This suggests that while genetic variation shapes the core protein-coding architecture, environmental exposures preferentially modify regulatory networks that control gene activity, often in regions showing coordinated changes in chromatin accessibility.

Cell-State Specificity of Epigenetic Effects

Cell-state specificity, environmental exposures were observed to have a more pronounced effect on naive lymphocytes, while genetic factors exerted a stronger influence on memory lymphocytes, reflecting the cumulative impact of inherited variation on long-lived immune cell states.

Immune Remodeling in HIV and COVID-19

COVID-19 and HIV impacts, prior HIV-1 infection was associated with substantial shifts in immune cell composition, particularly remodeling NK cells and memory T cells.

Regarding COVID-19, the analyses identified a specific monocyte cluster uniquely enriched in patients with severe disease. The statistical separation of this cluster was substantial (P = 2.05 × 10^-237), suggesting that these cells are strongly associated with inflammatory immune programs characteristic of severe COVID-19, without establishing a direct causal role in disease pathology.

Genetic Ancestry and Disease-Linked Epigenetic Variation

Ancestry and disease risks, genetic ancestry was found to influence immune epigenetic responses. In both MRSA and COVID-19 exposures, individuals of African genetic ancestry showed greater methylation changes than those of European ancestry, even after adjustment for covariates.

Furthermore, genotype-associated methylation signals overlapped with known disease-risk loci. Specifically, genetic variants associated with eczema and gallstone disease showed significant colocalization with methylation sites in T cells, linking immune epigenetic regulation to broader disease susceptibility.

Conclusions and Implications for Personalized Medicine

The present study provides evidence that nature and nurture are distinct architects of immune cell biology. Although their effects converge on immune function, genetic variation and environmental exposures appear to operate through mechanistically and genomically separate pathways.

The atlas has the potential to advance personalized medicine. Future research will be required to validate the biological and clinical relevance of specific eDMRs and gDMRs, clarify their functional consequences, and address current limitations, such as incomplete exposure histories, modest sample sizes in some exposure groups, and restricted longitudinal sampling, before they can be reliably deployed as high-accuracy biomarkers.