DNA Methylation Patterns in CD4+CD4+<math><mrow><mtext>CD</mtext><msup><mrow><mn>4</mn></mrow><mrow><mo>+</mo></mrow></msup></mrow></math> T Cells of Naïve and Influenza A Virus-Infected Mice Developmentally Exposed to an Aryl Hydrocarbon Receptor Ligand

Background: Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are CD4+CD4+$\text{CD}{4}^{+}$ T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of CD4+CD4+$\text{CD}{4}^{+}$ T cells to remain affected into adulthood remain unclear. Objective: Our goal was to identify cellular mechanisms that drive impaired CD4+CD4+$\text{CD}{4}^{+}$ T-cell responses later in life following maternal exposure to an exogenous AhR ligand. Methods: C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo-pp$p$-dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in CD4+CD4+$\text{CD}{4}^{+}$ T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of CD4+CD4+$\text{CD}{4}^{+}$ T cells from developmentally exposed mice to infection. Results: Gene and protein expression showed that developmental AhR activation reduced CD4+CD4+$\text{CD}{4}^{+}$ T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the CD4+CD4+$\text{CD}{4}^{+}$ T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired CD4+CD4+$\text{CD}{4}^{+}$ T-cell responses. Discussion: Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of CD4+CD4+$\text{CD}{4}^{+}$ T-cell functional responsiveness. https://doi.org/10.1289/EHP7699.