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Developmental Activation of the Aryl Hydrocarbon Receptor Results in Durable Changes to the Responsive Capacity and Epigenetic Landscape of CD4+ T Cells

URL to cite or link to: http://hdl.handle.net/1802/36437

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Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology and Immunology, 2019.
Early life environmental exposures have lasting effects on health and can contribute to disease, including changes to the function of immune cells. However, the cellular mechanisms that drive these durable changes remain poorly defined. Recently, we showed that activation of the aryl hydrocarbon receptor (AHR) during development impairs conventional CD4+ T cell responses to influenza A virus (IAV) infection in adult offspring. Adoptive transfers revealed these changes are due to direct effects in the CD4+ T cell lineage. The activation and differentiation of naïve CD4+ T cells into functionally distinct conventional subsets involves the integration of multiple signaling pathways, providing many different genes and cellular processes that could be affected by AHR activation during development. To identify the signaling pathways associated with altered CD4+ T cell functional capacity, we used RNA sequencing on sorted resting and responding CD4+ T cells from developmentally exposed mice during infection with IAV at adulthood. Differentially expressed genes were in pathways critical for CD4+ T cell activation, proliferation, differentiation, and metabolism. Using functional bioassays, CD4+ T cell from mature offspring that were developmentally exposed to the prototype AHR agonist, 2,3,7,8-tetrachloroibenzo-p-dioxin (TCDD), exhibit reduced proliferation, T helper subset differentiation, and cellular metabolism in vivo. These changes are laid down during development, are long lasting, and implicate altered epigenetic regulation as a potential mechanism. We utilized whole genome bisulfite sequencing to map how developmental exposure impacts DNA methylation in CD4+ T cells before and after infection. Developmental exposure results in hyper- and hypo- differential methylation patterns across the entire genome of CD4+ T cells. Treatment of developmentally exposed mice with the DNA methylation altering drugs S-adenosylmethionine (SAM) or zebularine restored some aspects of CD4+ T cell responses. These results indicate that altered DNA methylation is a mechanism by which AHR activation during development causes durable changes in antiviral immunity, and that hyper- and hypo-methylation regulate distinct aspects of CD4+ T cell responses to infection. Given that humans are regularly exposed to many different types of AHR ligands, this has far-reaching implications for how AHR signaling, particularly during development, durably influences T cell mediated immune responses.
Contributor(s):
Catherine G. Burke - Author

B. Paige Lawrence - Thesis Advisor

Primary Item Type:
Thesis
Language:
English
Subject Keywords:
AHR; Aryl hydrocarbon receptor; Development; Immunotoxicology; T cell
Sponsor - Description:
National Institute of Environmental Health Sciences (NIEHS) - R01ES017250; R01ES023260; R01ES004862; P30ES01247; T32ES007026;
National Institute of Allergy and Infectious Diseases (NIAID) - T32AI007285
First presented to the public:
12/31/2021
Originally created:
2019
Date will be made available to public:
2021-12-31   
Original Publication Date:
2019
Previously Published By:
University of Rochester School of Medicine and Dentistry
Place Of Publication:
Rochester, N.Y.
Citation:
Extents:
Illustrations - Illustrations : some color
Number of Pages - xxv, 249 pages
License Grantor / Date Granted:
Jennifer McCarthy / 2021-07-21 14:46:13.145 ( View License )
Date Deposited
2021-07-21 14:46:13.145
Submitter:
Jennifer McCarthy

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