Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8+ T cell responses

J Immunol. 2015 May 1;194(9):4446-57. doi: 10.4049/jimmunol.1402044. Epub 2015 Mar 25.


Successfully fighting infection requires a properly tuned immune system. Recent epidemiological studies link exposure to pollutants that bind the aryl hydrocarbon receptor (AHR) during development with poorer immune responses later in life. Yet, how developmental triggering of AHR durably alters immune cell function remains unknown. Using a mouse model, we show that developmental activation of AHR leads to long-lasting reduction in the response of CD8(+) T cells during influenza virus infection, cells critical for resolving primary infection. Combining genome-wide approaches, we demonstrate that developmental activation alters DNA methylation and gene expression patterns in isolated CD8(+) T cells prior to and during infection. Altered transcriptional profiles in CD8(+) T cells from developmentally exposed mice reflect changes in pathways involved in proliferation and immunoregulation, with an overall pattern that bears hallmarks of T cell exhaustion. Developmental exposure also changed DNA methylation across the genome, but differences were most pronounced following infection, where we observed inverse correlation between promoter methylation and gene expression. This points to altered regulation of DNA methylation as one mechanism by which AHR causes durable changes in T cell function. Discovering that distinct gene sets and pathways were differentially changed in developmentally exposed mice prior to and after infection further reveals that the process of CD8(+) T cell activation is rendered fundamentally different by early life AHR signaling. These findings reveal a novel role for AHR in the developing immune system: regulating DNA methylation and gene expression as T cells respond to infection later in life.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • DNA Methylation*
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Male
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Receptors, Aryl Hydrocarbon / genetics*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Virus Diseases / genetics*
  • Virus Diseases / immunology*
  • Virus Diseases / metabolism


  • Receptors, Aryl Hydrocarbon

Associated data

  • GEO/GSE60115