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Research Article Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1408110

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

Lisbeth A. Boule,1 Bethany Winans,2 and B. Paige Lawrence1,2
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1Department of Microbiology and Immunology and 2Department of Environmental Medicine, University of Rochester, Rochester, New York, USA
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Boule LA, Winans B, Lawrence BP. Effects of Developmental Activation of the AhR on CD4+ T-Cell Responses to Influenza Virus Infection in Adult Mice. Environ Health Perspect;

Received: 10 January 2014
Accepted: 21 July 2014
Advance Publication: 22 July 2014

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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: C57B1/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in utero and via suckling. CD4+ T cell activation and differentiation into distinct effector populations was measured 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 exposure on CD4+ T cells.

Results: Developmental exposure skewed CD4+ T cell responses to IAV infection. There were 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. Impaired differentiation into conventional effector subsets was due to direct effects of AhR activation on CD4+ T cells, as this defect can be transferred to mice that had not been developmentally exposed to TCDD.

Conclusions: Maternal exposure to TCDD causes durable changes in the responsive capacity and differentiation of CD4+ T cells in adult C57Bl/6 mice.

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