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Production of extracellular adenosine by CD73+ dendritic cells is crucial for induction of tolerance in contact hypersensitivity reactions

Dendritic cells (DCs) express the ecto-5′-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73-derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applie...

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Main Authors: Silva-Vilches, Cinthia (Author) , Ring, Sabine (Author) , Enk, Alexander (Author) , Mahnke, Karsten (Author)
Format: Article (Journal)
Language:English
Published: 2019
In: The journal of investigative dermatology
Year: 2018, Volume: 139, Issue: 3, Pages: 541-551
ISSN:1523-1747
DOI:10.1016/j.jid.2018.10.016
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.jid.2018.10.016
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0022202X18327088
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Author Notes:Cinthia Silva-Vilches, Sabine Ring, Jürgen Schrader, Björn E. Clausen, Hans-Christian Probst, Felix Melchior, Hansjörg Schild, Alexander Enk and Karsten Mahnke

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520 |a Dendritic cells (DCs) express the ecto-5′-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73-derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wild-type (WT) or CD73-deficient (CD73-/-) mice, followed by sensitization and challenge with 2,4-dinitrofluorobenzene. In this model, we show the induction of tolerance by DNTB against 2,4-dinitrofluorobenzene only in WT but not in CD73-/- mice. Analysis of skin DCs showed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrations of extracellular Ado in the lymph node. Moreover, T cells expressed markers for anergy, namely EGR2 and NDRG1 in DNTB-treated WT mice and they exhibited impaired proliferation upon ex vivo re-stimulation. Similarly, in vitro we observed that Ado-producing WT DCs, but not CD73-/- DCs, rendered transgenic T cells from OTII mice (OTII T cells) hyporeactive, decreased their T-cell costimulatory signaling, and induced up-regulation of EGR2 and NDRG1. Thus, these data show that expression of CD73 by DCs, which triggers elevated levels of extracellular Ado, is a crucial mechanism for the induction of anergic T cells and tolerance. 
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