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Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral T cell responses [RNA-Seq]

ABSTRACT: 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 immune cells respond to viral infection later in life.

ORGANISM(S): Mus musculus

PROVIDER: GSE60114 | GEO | 2015/03/16

SECONDARY ACCESSION(S): PRJNA257507

REPOSITORIES: GEO

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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.

Project description:Understanding the mechanisms of host macrophage responses to M. tuberculosis (M.tb.) is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed M.tb. infection strongly induced expression of several enzymes controlling tryptophan (Trp) catabolism. This included indole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator (ARNT) and RELB are robustly expressed, and AHR and RELB levels further increased during infection. Infection enhanced AHR/ARNT and AHR/RELB DNA binding, and stimulated expression of AHR target genes, including that encoding the inflammatory cytokine IL1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous Trp, kynurenine or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced expression of IL23A and IL12B transcripts, which encode subunits of interleukin 23 (IL23), a macrophage cytokine that stimulates production of IL22 by innate lymphoid cells. The AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in Mtb-infected macrophages, and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, as IL1B (IL-1β) and IL23 stimulate T cell subsets producing IL22, another direct target of AHR transactivation. Gene expression profiling of Mtb-infected THP-1 monocytic cells following siRNA-mediated Aryl hydrocarbon receptor (AHR) knockdown.

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Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral T cell responses [RNA-Seq]

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