Stem cell transplantation uncovers TDO-AHR regulation of lung dendritic cells in herpesvirus-induced pathology
Stephen J. Gurczynski, Nicolas L. Pereira, Steven M. Hrycaj, Carol Wilke, Rachel L. Zemans, Bethany B. Moore
Stephen J. Gurczynski, Nicolas L. Pereira, Steven M. Hrycaj, Carol Wilke, Rachel L. Zemans, Bethany B. Moore
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Research Article Immunology Transplantation

Stem cell transplantation uncovers TDO-AHR regulation of lung dendritic cells in herpesvirus-induced pathology

Abstract

The aryl-hydrocarbon receptor (AHR) is an intracellular sensor of aromatic hydrocarbons that sits at the top of various immunomodulatory pathways. Here, we present evidence that AHR plays a role in controlling IL-17 responses and the development of pulmonary fibrosis in response to respiratory pathogens following bone marrow transplant (BMT). Mice infected intranasally with gamma-herpesvirus 68 (γHV-68) following BMT displayed elevated levels of the AHR ligand, kynurenine (kyn), in comparison with control mice. Inhibition or genetic ablation of AHR signaling resulted in a significant decrease in IL-17 expression as well as a reduction in lung pathology. Lung CD103+ DCs expressed AHR following BMT, and treatment of induced CD103+ DCs with kyn resulted in altered cytokine production in response to γHV-68. Interestingly, mice deficient in the kyn-producing enzyme indolamine 2-3 dioxygenase showed no differences in cytokine responses to γHV-68 following BMT; however, isolated pulmonary fibroblasts infected with γHV-68 expressed the kyn-producing enzyme tryptophan dioxygenase (TDO2). Our data indicate that alterations in the production of AHR ligands in response to respiratory pathogens following BMT results in a pro-Th17 phenotype that drives lung pathology. We have further identified the TDO2/AHR axis as a potentially novel form of intercellular communication between fibroblasts and DCs that shapes immune responses to respiratory pathogens.

Authors

Stephen J. Gurczynski, Nicolas L. Pereira, Steven M. Hrycaj, Carol Wilke, Rachel L. Zemans, Bethany B. Moore

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Figure 7

Ablation of IDO does not alter Th17 differentiation, IL-17 production, or fibrotic pathology in response to γHV-68 following BMT.

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Ablation of IDO does not alter Th17 differentiation, IL-17 production, o...
(A) Groups of mice were analyzed for expression of IDO in whole-lung homogenate 7 days following γHV-68 infection (shown as mean ± SEM, n = 5 mice per group). (B and C) Lung leukocytes were isolated from collagenase-digested lung 7 days following γHV-68 infection (shown as mean ± SEM, WT, BMT, and IDO–/– — BMT n = 8 mice per group, IDO–/– — IDO–/– n = 3 mice per group; the dashes signify the BMT pairing that was performed, with the donor cells denoted to the left of the dash and the recipient mouse strain on the right). Numbers of Th17 and Th1 cells were analyzed by ICS and flow cytometry. (D) Representative micrographs of sectioned lung tissue from the indicated transplant, stained with H&E. Original magnification, ×10. (E–G) Expression of indicated transcript was analyzed in lung leukocytes obtained from groups of mice at 7 dpi by qRT-PCR (shown as mean ± SEM, panel E WT n = 10, BMT, n = 10, IDO–/– — BMT n = 5. Panels F and G n = 5 mice per group). (H) Concentration of kyn was analyzed in whole-lung homogenates at 7 dpi via ELISA (shown as mean ± SEM, WT, BMT, and IDO–/– — BMT n = 8 mice per group, IDO–/– — IDO–/– n = 3 mice per group). Statistical significance was determined by ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001.