The ecto-5'-nucleotidase CD73 converts extracellular adenosine monophosphate, which is a product of ATP degradation by CD39, to adenosine (ADO). Because ADO has well established anti-inflammatory effects, expression of CD73 by different types of skin cells may be crucial for the outcome of contact hypersensitivity (CHS) reactions. At first we analysed expression of CD39 and CD73, respectively, by different subsets of skin dendritic cells (DCs) and found ubiquitous expression of CD39 on all defined DC subsets. In contrast, CD73 was expressed by only 3%-8% of CD207+ Langerhans cells (LC) and other dermal DCs, respectively. Similar expression patterns were observed in skin migrating (sm) DCs in the lymph node under steady state conditions. However, application of the hapten TNCB induced surface-expression of CD73 in all cells, resulting in 20%-30% CD73+ DC and LC, respectively. This increased expression of CD73 was persistent, as it was also detectable in smDC 24h-48h after sensitization. Next, CD73 deficient (CD73KO) mice were subjected to a classical TNCB-induced CHS protocol and we found increased ear swelling reactions as compared to wild type mice, indicating rather down-modulatory functions of CD73 in CHS reactions. To accurately assess the tolerogenic functions of CD73 expression by smDC in CHS reactions, we established a tolerance model whereby application of DNTB renders animals tolerant to subsequent sensitization with DNFB. Here we show that both, the tolerogen DNTB as well as the sensitizer DNFB induced migration of similar DC subsets from skin to lymph nodes. But after DNTB application substantially higher expression levels of CD73 was observed in particular in CD11b+ as well as in CD207+CD103+ smDC. Of note, CD73KO animals were resistant to tolerization by DNTB. Thus, these data indicate a substantial role of CD73+ skin DC in regulating tolerance to haptens.