Developmental Origins of Delayed Adult Immune Response: The AhR Connection.

Numerous epidemiological and experimental studies indicate that early life environmental exposures influence health and disease later in life.1 Environmental exposures can also influence the immune system, and studies suggest even subtle changes may diminish resistance to infectious disease,2,3,4 reduce vaccine efficacy,5,6 dampen tumor surveillance,7 and cause autoimmune and allergic diseases.8,9 Building on evidence that developmental exposure to pollutants that bind to the aryl hydrocarbon receptor (AhR) causes lasting changes in immune function,2,3,4 a report published in Environmental Health Perspectives examined how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects T-cell function.10

Much of what we know about the AhR and the immune system comes from looking at direct exposures to the mature immune system. But rodent studies of prenatal and early-life exposures show new evidence for potential mechanisms behind chemical-induced developmental immunotoxicity. © Pacific Press/Science Source.

TCDD toxicity is mediated through activation of the AhR, a protein of ancient origins that acts as an environmental sensor for the proper functioning of cells and organs.7 Its evolutionary conservation and broad expression in the immune system have prompted numerous studies into the role of AhR in immune function.11 However, much of what is known about the AhR and the immune system is based on the evaluation of direct exposure to the mature immune system, not in the context of developmental exposure, says B. Paige Lawrence, a professor in the Department of Environmental Medicine at the University of Rochester and senior author of the new study.

To examine how developmental exposure affects the responsive capacity of the offspring’s immune system, the research team exposed mice during gestation and early lactation. They then challenged the adult offspring with influenza A virus. Finally, they compared the transcriptome (all the mRNA expressed by the mice), genomewide DNA methylation, and function of CD4+ T cells in infected animals to those of uninfected offspring from control and TCDD-treated dams.

TCDD exposure during development induced important differences in DNA methylation that lasted long after exposure ended. These differences were, at least in part, responsible for variances between how the treated mice responded to infection compared with controls. After infection, both groups of mice had additional differences in DNA methylation, compared with those exposed to TCDD without infection. However, TCDD-treated mice had 20% more regions of DNA where the methylation pattern was altered in the face of a challenge, compared with controls.

The investigators also found evidence suggesting that the differences in response capacity of CD4+ T cells could be modified later in life. They gave the offspring drugs that either boost or dampen overall DNA methylation, which alleviated some of the deficits in T cell responses to infection. Lawrence says this indicates that human studies on phenotypic profiles, gene expression, or DNA methylation patterns in circulating T cells may be obtaining incomplete or inaccurate information if T cells are not activated.

Although AhR is perhaps best known for its role in mediating the chemical toxicity of environmental contaminants, focus is now shifting toward its response to endogenous signals. AhR activation has been linked to control of cell differentiation and pluripotency,12 implicating it in autoimmune and degenerative diseases, as well as cancer.

The initial research on AhR activation via toxicants opened the door to studies into other ligands and their relevance to human disease, says Francisco Quintana, a professor of neurology at Harvard Medical School who was not involved in the new study. Quintana posits that the effects observed in this study could help elucidate how exposure to pollutants affect differential responses of the immune system to infections or tumors. He suggests that future studies should aim to recapitulate whether these effects are applicable to endogenous chemicals, too.