Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection

Abstract

It has long been known that activation of the aryl hydrocarbon receptor (AhR) by ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses T cell-dependent immune responses; however, the underlying cellular targets and mechanism remain unclear. We have previously shown that AhR activation by TCDD reduces the proliferation and differentiation of influenza virus-specific CD8(+) T cells through an indirect mechanism; suggesting that accessory cells are critical AhR targets during infection. Respiratory dendritic cells (DCs) capture antigen, migrate to lymph nodes, and play a key role in activating naive CD8(+) T cells during respiratory virus infection. Herein, we report an examination of how AhR activation alters DCs in the lung and affects their trafficking to and function in the mediastinal lymph nodes (MLN) during infection with influenza virus. We show that AhR activation impairs lung DC migration and reduces the ability of DCs isolated from the MLN to activate naive CD8(+) T cells. Using novel AhR mutant mice, in which the AhR protein lacks its DNA-binding domain, we show that the suppressive effects of TCDD require that the activated AhR complex binds to DNA. These new findings suggest that AhR activation by chemicals from our environment impacts DC function to stimulate naive CD8(+) T cells and that immunoregulatory genes within DCs are critical targets of AhR. Moreover, our results reinforce the idea that environmental signals and AhR ligands may contribute to differential susceptibilities and responses to respiratory infection.

Activation of the Arylhydrocarbon Receptor Causes Immunosuppression Primarily by Modulating Dendritic Cells

“…In line with previous reports (Jin et al, 2010;Quintana et al, 2010), we already provided preliminary evidence that NP suppresses the immune system by primarily acting on DC, as s.c. injection of hapten-coupled BMDCs, which were treated with NP, lost the capacity to induce sensitization but in turn induced Treg. These findings were confirmed in the present work.…”

Cross-talk between Aryl Hydrocarbon Receptor and the Inflammatory Response

“…The AhR affects the expression of immunoregulatory genes and the function as well as differentiation of inflammatory DC (5)(6)(7)(8). Furthermore, recent reports show that the AhR plays a critical role in T-cell differentiation and immunity of the gut (9 -12), but the molecular mechanisms that control its activity in immune cells during inflammation have remained unclear.…”

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

“…19 TCDD also inhibited DC activation of CD8 + T cells during the Th1-mediated response to influenza infection. 20 However, these studies may be limited by the use of TCDD as a model AhR ligand. 21 TCDD has a higher affinity for the AhR and a longer half-life than naturally occurring ligands, 21 and the signals it delivers are qualitatively as well as quantitatively different from naturally occurring and endogenous ligands.…”