Effects of Developmental Activation of the AhR on CD4(+) T-Cell Responses to Influenza Virus Infection in Adult Mice

Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4(+) T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4(+) T cells has not been directly examined. Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4(+) T cell differentiation and function later in life. Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4(+) T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4(+) T-cell responses resulted from direct effects of developmental TCDD exposure on CD4(+) T cells. Results: Developmental exposure skewed CD4(+) T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4(+) T cells and a reduced frequency of conventional CD4(+) effector-cell subsets. However, there was an increase in regulatory CD4(+) T cells. Direct effects of AhR activation on CD4(+) T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD. Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4(+) T cells in adult C57BL/6 mice. Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4(+) T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110