Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Abstract

The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR−/−→CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon

“…AhR also regulates the host response to virus infection. Treatment of mice with a low dose of the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin increased morbidity and mortality in mice infected with influenza A virus (69), by impairing the priming of CD8ϩ T cells in the lung (70). Given the broad roles of AhR in the regulation of multiple facets of immune cell development, activation, and differentiation, it will be interesting to determine whether AhR inhibits innate antiviral signaling and type I IFN together with AIP.…”

Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function

“…10,15,16 However, when using whole animal models, it is difficult to determine whether the effects of AhR ligands are due to direct effects on T cells or to effects on T-cell programming by antigen-presenting cells. Interestingly, wild-type recipients of adoptively transferred AhR-deficient T cells displayed TCDD-induced inhibition of T-cell proliferation in response to influenza virus, 11,17 suggesting that antigenpresenting cells play a key a role in AhR modulation of T-cell function.…”

Memory CD8+T Cells Are Sufficient To Alleviate Impaired Host Resistance to Influenza A Virus Infection Caused by Neonatal Oxygen Supplementation

“…Antibodies were obtained from eBiosciences. Major histocompatibility complex (MHC) class I tetramers for influenza A virus nucleoprotein (D b /NP 366 -374 ) and acid polymerase (D b /PA 224 -233 ) were used to identify CD8 ϩ T cells specific for immunodominant viral epitopes (25). Live/ Dead (Invitrogen) and 7-aminoactinomycin D (7-AAD; BD Biosciences) stains were used according to the manufacturers' instructions and provided a means to exclude dead cells during analysis.…”