Activation of the aryl hydrocarbon receptor diminishes the memory response to homotypic influenza virus infection but does not impair host resistance.

Abstract

Although suppression of a primary immune response by aryl hydrocarbon receptor (AhR) ligands is well known, few studies have explicitly examined the effects of AhR agonists on immunological memory. Therefore, the goal of this study was to characterize the anamnestic response to influenza virus in mice exposed to the most potent AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mice were given a single dose of TCDD, which caused suppression of the primary response, and kinetics of the recall antibody and CD8(+) T cell responses to homotypic infection were monitored. Two to three months after primary infection, virus-specific IgG levels were suppressed in mice treated with TCDD, and remained suppressed after reinfection. In contrast, IgA levels were enhanced in the TCDD-treated group. The recall response of virus-specific CD8(+) T cells was also suppressed, as the number of virus-specific memory CD8(+) T cells was diminished, and the kinetics of the recall response was delayed. No morbidity or mortality was observed in vehicle- or TCDD-treated mice, and mice in both groups cleared the virus within three days after reinfection. Thus, with regard to understanding how activation of the AhR during a primary immune response affects the generation of immunological memory, our data present a mixed story. On one hand, TCDD treatment reduced the primary response, resulting in lower levels of virus-specific IgG and diminution of the memory CD8 pool. However, the secondary response to homotypic infection was nevertheless host-protective. These findings have implications for determining the mechanisms by which AhR ligands adversely affect lymphocyte function and understanding the mechanisms that control the acquisition of immunological memory.