In vivo activation of the aryl hydrocarbon receptor during viral infection up-regulates immunoregulatory factors in dendritic cells (IRC10P.411)

Activation of the aryl hydrocarbon receptor (AHR) substantially dampens host resistance to infection with influenza A viruses. We previously reported that AHR activation negatively regulates the expansion and differentiation of CD8 + cytotoxic T lymphocytes (CTL), and reduces the ability of dendritic cells (DC) to prime naive CD8 T cells. However, the mechanism by which AHR activation dampens DC function in vivo is unknown. Given that AHR is a ligand inducible transcription factor, we used unbiased gene expression profiling to identify DC specific pathways modulated by in vivo AHR activation. Lung DCs from mice that were exposed to the prototype AHR ligand 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) or control were sorted and used for unbias transcriptome analysis with RNA-seq. This approach revealed multiple gene targets of AHR in DCs, which may play a role in modulating DC function. For example, indoleamine-2,3-dioxygenase ( Ido1 ) was highly induced. Accompanying increased Ido1 expression were significant increases in the proportion of plasmacytoid DCs (pDCs) and regulatory T cells. Expanding our findings into an in vitro human system, monocyte-derived DCs from healthy human donors exposed to TCDD and influenza A virus presented a similar suite of altered genes, including elevated Ido1 . This is further evidence that AHR activation in DCs intrinsically changes gene expression, inducing an immunoregulatory phenotype that exerts strong influence on the antiviral immune response.