New insights into the role of the aryl hydrocarbon receptor in the function of CD11c⁺ cells during respiratory viral infection

Abstract

Summary The aryl hydrocarbon receptor (AHR) has garnered considerable attention as a modulator of CD4 lineage development and function. It also regulates antiviral CD8+ T cell responses, but via indirect mechanisms that have yet to be determined. Here, we show that during acute influenza virus infection, AHR activation skews dendritic cell (DC) subsets in the lung-draining lymph nodes, such that there are fewer conventional CD103+DCs and CD11b+DCs. Sorting DC subsets reveals AHR activation reduces immunostimulatory function of CD103+DCs in the MLN, and decreases their frequency in the lung. DNA binding domain (DBD) Ahr mutants demonstrate that alterations in DC subsets require the ligand-activated AHR to contain its inherent DBD. To evaluate the intrinsic role of AHR in DCs, conditional knockouts were created using Cre-LoxP technology, which reveal that AHR in CD11c+ cells plays a key role in controlling the acquisition of effector CD8+ T cells in the infected lung. However, AHR within other leukocyte lineages contributes to diminished naïve CD8+ T cell activation in the draining lymphoid nodes. These findings indicate DCs are among direct targets of AHR ligands in vivo, and AHR signaling modifies host responses to a common respiratory pathogen by affecting the complex interplay of multiple cell types.

Effects of Developmental Activation of the AhR on CD4 + T-Cell Responses to Influenza Virus Infection in Adult Mice

“…B cells and APCs express the AhR, and their function is modulated by AhR activation in adult animals (Jin et al 2014; Quintana and Sherr 2013; Sulentic and Kaminski 2011). Non-hematopoietic cells are also important for CD4 + T-cell development and function (Mebius 2003).…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…The AhR is a modulator of antiviral immunity in the lung. In particular, the work by the group of Paige Lawrence demonstrated the complex relationship of AhR-mediated events in CD8 T cells, DCs, neutrophils, and lung epithelium in influenza A virus-infected mice (Vorderstrasse et al, 2003;Jin et al, 2014). AhR activation by TCDD decreased survival from infection with a nonlethal dose of influenza A virus (Vorderstrasse et al, 2003), accompanied by doubled pulmonary neutrophil influx and suppression of expansion and differentiation of virus-specific effector CD8 + T cells (Lawrence et al, 2006).…”

“…AhR activation by TCDD decreased survival from infection with a nonlethal dose of influenza A virus (Vorderstrasse et al, 2003), accompanied by doubled pulmonary neutrophil influx and suppression of expansion and differentiation of virus-specific effector CD8 + T cells (Lawrence et al, 2006). At the same time, AhR activation decreased the immunostimulatory function of DCs in lung-draining lymph nodes and reduced their frequency in the lungs (Wheeler et al, 2013;Jin et al, 2014). Neutrophil influx is mediated by the AhR in the lung epithelium because conditional AhR-deficient mice (lacking the AhR only in lung epithelium) had no increased neutrophil influx upon TCDD exposure.…”

Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection

“…The frozen stocks were titered by viable plate counts, and, when needed for infection, a stock tube was thawed and diluted in PBS/0.05% Tween 80 for an intranasal dose of 1 ϫ 10 6 colonyforming unit BCG in 25 l. At specified points in time, lungs were perfused, and lungs, spleens, and lymph nodes were removed. Singlecell suspensions were prepared as previously described (23,30,42). In separate experiments, cells from the airways were collected by bronchoalveolar lavage (BAL), as previously described (43).…”