Postnatal administration of S-adenosylmethionine restores developmental AHR activation-induced deficits in CD8+ T cell function during influenza A virus infection

ABSTRACT: Developmental exposures can influence life-long health; yet, approaches to counteract negative consequences of developmental toxicity are limited due to poor understanding of cellular mechanisms. The aryl hydrocarbon receptor (AHR) binds many small molecules, including numerous pollutants. Developmental exposure to the signature environmental AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly dampens the adaptive immune response to influenza A virus (IAV) in adult offspring. CD8+ cytotoxic T lymphocytes (CTL) are crucial for successful resolution. Their effectiveness depends not only on the number generated, but also on the complexity of their functionality; that is, polyfunctional CD8+ T cells are more effective. Prior studies showed that developmental AHR activation significantly reduced the number of virus-specific CD8+ T cells during infection, but the impact on CD8+ T cell functions is less clear. Other studies showed that developmental exposure was associated with differences in DNA methylation in CD8+ T cells. Yet, empirical evidence that differences in DNA methylation are causally related to altered CD8+ T cell function is lacking. Accordingly, there were two main objectives: to ascertain whether developmental AHR activation affects CTL function, and to determine whether differences in DNA methylation contribute to the reduced CD8+ T cell response to infection. Flow cytometry and Simplified Presentation of Incredibly Complex Evaluations (SPICE) were used to measure CD8+ T functions, including CTL polyfunctionality. Triggering AHR during development significantly reduced CTL polyfunctionality. Developmentally exposed mice were treated with S-adenosylmethionine (SAM), to increase DNA methylation, or Zebularine, to diminish DNA methylation. SAM restored CTL polyfunctionality and boosted the number of virus-specific CD8+ T cells. Zebularine did not attenuate the impact of maternal TCDD treatment on the CTL response. These results indicate that DNA hypomethylation, initiated by developmental exposure to an AHR-binding chemical, contributes to durable changes in antiviral CD8+ CTL responsive capacity later in life. Thus, deleterious consequence of development exposure to environmental chemicals are not permanently fixed, opening the door for interventional strategies to improve health.

ORGANISM(S): Mus musculus

PROVIDER: GSE216755 | GEO | 2023/03/06

REPOSITORIES: GEO