Production of Extracellular Adenosine by CD73+ Dendritic Cells Is Crucial for Induction of Tolerance in Contact Hypersensitivity Reactions

• Published in: Journal of investigative dermatology Vol. 139; no. 3; pp. 541 - 551
• Main Authors: Silva-Vilches, Cinthia, Ring, Sabine, Schrader, Jürgen, Clausen, Björn E., Probst, Hans-Christian, Melchior, Felix, Schild, Hansjörg, Enk, Alexander, Mahnke, Karsten
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: 5'-Nucleotidase - immunology; Adenosine - metabolism; Animals; Cells, Cultured; Dendritic Cells - immunology; Dermatitis, Allergic Contact - immunology; Dermatitis, Allergic Contact - pathology; Disease Models, Animal; Flow Cytometry; GPI-Linked Proteins - immunology; Immune Tolerance - immunology; Immune Tolerance - physiology; Mice; Mice, Knockout; Random Allocation; Real-Time Polymerase Chain Reaction - methods; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; OTII; LN; AMP; DNFB; Treg; iDC; cAMP; smDC; Ado; mDC; BMDC; LC; DNTB; Ova; ATP; WT; DC
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2018.10.016

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.