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The CD83 molecule is a novel target gene for the aryl hydrocarbon receptor in human dendritic cells

Michalski, J;

1.1 Summary

Project 1:
The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) is a promising
therapeutic target for the regulation of dendritic cell (DC)-mediated antigen-specific tolerance
in autoimmune diseases. Bioinformatic analyses identified two AHR binding motifs within the
CD83 promoter region of human DCs, thereby making CD83 to a potential AHR target gene.
Our group showed that the natural low-affinity AHR ligand quercetin impaired the CD83
upregulation in human LPS-matured monocyte-derived DCs (LPS-DCs), and that quercetintreated
LPS-DCs secreted higher levels of IL-1ß, IL-8, TNF-α but lower levels of IL-12p70. In
the present study, we compared the synthetic high-affinity ligand TCDD to quercetin to gain
more insights into the effects of AHR activation on human DCs. TCDD impaired the CD83
expression in LPS-DCs and altered their cytokine profile similar to quercetin, but IL-12p70
levels were increased. The CD83 suppression induced by both ligands was reversed by the
AHR antagonist SR1. Moreover, CD83 transcription was regulated by the binding of AHR to
the CD83 promoter. Notably, quercetin, but not TCDD, led to a reduced T cell stimulatory
capacity of LPS-DCs and to a higher frequency of regulatory T cells. Quercetin additionally
induced the expression of ILT2, ILT3, ILT4, ILT5 as well as CD39 and CD73 in LPS-DCs,
thereby pointing to a tolerogenic phenotype. Finally, quercetin reduced the pathology in the
murine experimental autoimmune encephalomyelitis (EAE) model. Overall, the data provide
phenotypic and functional evidence that quercetin induces tolerogenic properties in human
DCs, thereby identifying a potential immunomodulatory agent.

Project 2:
The CD83 molecule has been related to cancer due to its expression by several tumor cells
and soluble CD83 has been described to be present at elevated levels in haematological
malignancies such as Hodgkin lymphoma, thereby representing a potential new biomarker.
However, it was not known whether CD83 could also be a biomarker for malignant
melanoma. Thus, this project aimed to examine the prognostic/diagnostic relevance of CD83
expression on malignant melanoma cells. Therefore, different available melanoma cell lines
and patient-derived melanoma cell lines were investigated for their CD83 expression.
However, if at all melanoma cells expressed only very low CD83 levels. Even stimulation with
PMA and ionomycin or incubation with dabrafenib and/or trametinib did not trigger CD83
expression by the used cells lines. Altogether, from these data we conclude that CD83 does
not represent a biomarker for malignant melanoma.