Dataset Information

Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice.

ABSTRACT:

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.

SUBMITTER: Boule LA

PROVIDER: S-EPMC4216167 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice.

Boule Lisbeth A LA Winans Bethany B Lawrence B Paige BP

Environmental health perspectives 20140722 11

<h4>Background</h4>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.<h4>Objectives</h4>Our goal was to determine ...[more]

PMID: 25051576

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Project description: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.

Dataset Information

Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice.

Background

Objectives

Methods

Results

Conclusions

Publications

Effects of developmental activation of the AhR on CD4+ T-cell responses to influenza virus infection in adult mice.

Similar Datasets

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