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.
Although immune modulation by AhR ligands has been studied for many years, the impact of AhR activation on host defenses against viral infection has not, until recently, garnered much attention. The development of novel reagents and model systems, new information regarding antiviral immunity, and a growing appreciation for the global health threat posed by viruses have invigorated interest in understanding how environmental signals affect susceptibility to and pathological consequences of viral infection. Using influenza A virus as a model of respiratory viral infection, recent studies show that AhR activation cues signaling events in both leukocytes and non-immune cells. Functional alterations include suppressed lymphocyte responses and increased inflammation in the infected lung. AhR-mediated events within and extrinsic to hematopoietic cells has been investigated using bone marrow chimeras, which show that AhR alters different elements of the immune response by affecting different tissue targets. In particular, suppressed CD8 + T cell responses are due to deregulated events within leukocytes themselves, whereas increased neutrophil recruitment to and IFN-γ levels in the lung result from AhR-regulated events extrinsic to bone marrow-derived cells. This latter discovery suggests that epithelial and endothelial cells are overlooked targets of AhR-mediated changes in immune function. Further support that AhR influences host cell responses to viral infection are provided by several studies demonstrating that AhR interacts directly with viral proteins and affects viral latency. While AhR clearly modulates host responses to viral infection, we still have much to understand about the complex interactions between immune cells, viruses, and the host environment.
There are many known factors that can affect immune responses to respiratory viral infections such as influenza A virus. Indeed, recent epidemiological studies indicate that in addition to host genetics, age and pathogen sub-types, a variety of environmental factors also impact the immune response to infections. Many of these environmental factors, including diesel exhaust and cigarette smoke, contain ligands for the aryl hydrocarbon receptor (AhR), an environment-sensing transcription factor shown to affect multiple facets of the immune system. Our laboratory has shown that activation of the AhR by the persistent environmental contaminant dioxin exacerbates neutrophil recruitment and increases the expression of inducible nitric oxide synthase (iNOS) in the lungs of influenza virus-infected mice. We show that depleting neutrophils during viral infection does not abrogate AhR-mediated increases in iNOS expression, demonstrating that neutrophil recruitment is downstream of elevated iNOS. We also show that AhR activation in iNOS-deficient mice infected with influenza virus does not affect neutrophil recruitment to the lung. Thus, these findings suggest that these AhR-mediated events are linked, and that increased iNOS expression could be a novel mechanism regulating neutrophil migration the infected lung. Additionally these studies implicate iNOS as a novel AhR target gene and provide new insights into the mechanisms underlying leukocyte recruitment during viral infections.
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